Substituted tetrahydrocarbazole and carbazole carboxamide compounds

ABSTRACT

Disclosed are compounds of Formula (I) 
     
       
         
         
             
             
         
       
     
     wherein: the two dotted lines represent either two single or two double bonds; Q is: 
     
       
         
         
             
             
         
       
     
     R 1  is F, Cl, —CN, or —CH 3 ; R 2  is Cl or —CH 3 ; R 3  is —C(CH 3 ) 2 OH or —CH 2 CH 2 OH; R a  is H or —CH 3 ; each R b  is independently F, Cl, —CH 3 , and/or —OCH 3 ; and n is zero, 1, or 2. Also disclosed are methods of using such compounds as inhibitors of Bruton&#39;s tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/625,417, filed Jun. 16, 2017, which is acontinuation application of U.S. patent application Ser. No. 15/067,915,filed Mar. 11, 2016, which is a continuation application of U.S. patentapplication Ser. No. 14/314,602 filed Jun. 25, 2014, which claimspriority to U.S. Provisional Application 61/839,141, filed Jun. 25,2013, the contents of which are herein incorporated by reference intheir entirety.

DESCRIPTION

The present invention generally relates to substitutedtetrahydrocarbazole and carbazole carboxamide compounds useful as kinaseinhibitors, including the modulation of Bruton's tyrosine kinase (Btk)and other Tec family kinases such as Itk. Provided herein aresubstituted tetrahydrocarbazole and carbazole carboxamide compounds,compositions comprising such compounds, and methods of their use. Theinvention further pertains to pharmaceutical compositions containing atleast one compound according to the invention that are useful for thetreatment of conditions related to kinase modulation and methods ofinhibiting the activity of kinases, including Btk and other Tec familykinases such as Itk, in a mammal.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Btk is a member of the Tec family of tyrosinekinases, and is a regulator of early B-cell development, as well asmature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide rangeof biological outputs, which in turn depend on the developmental stageof the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice are also resistant to developingcollagen-induced arthritis and are less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as RITUXAN®) developed todeplete B-cells, represent an important approach to the treatment of anumber of autoimmune and/or inflammatory diseases. Because of Btk's rolein B-cell activation, inhibitors of Btk can be useful as inhibitors ofB-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseasesincluding, but not limited to: SLE, rheumatoid arthritis, multiplevasculitides, idiopathic thrombocytopenic purpura (ITP), myastheniagravis, allergic rhinitis, multiple sclerosis (MS), transplantrejection, type I diabetes, membranous nephritis, inflammatory boweldisease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold andwarm agglutinin diseases, Evans syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis,Sjögren's syndrome, peripheral neuropathies (e.g., Guillain-Barresyndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cellsurvival in certain B-cell cancers. For example, Btk has been shown tobe important for the survival of BCR-Abl-positive B-cell acutelymphoblastic leukemia cells. Thus inhibition of Btk activity can beuseful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of protein kinases, it is immediatelyapparent that new compounds capable of modulating protein kinases suchas Btk and methods of using these compounds should provide substantialtherapeutic benefits to a wide variety of patients.

U.S. Pat. No. 8,084,620 and WO 2011/159857 disclose tricycliccarboxamide compounds useful as kinase inhibitors, including themodulation of Btk and other Tec family kinases.

There still remains a need for compounds useful as Btk inhibitors andyet having selectivity over Jak2 tyrosine kinase. Further, there stillremains a need for compounds useful as Btk inhibitors that haveselectivity over Jak2 tyrosine kinase and also have improved potency inthe whole blood BCR-stimulated CD₆₉ expression assay.

Applicants have found potent compounds that have activity as Btkinhibitors. Further, applicants have found compounds that have activityas Btk inhibitors and are selective over Jak2 tyrosine kinase. Furtherstill, applicants have found compounds that have activity as Btkinhibitors, are selective over Jak2 tyrosine kinase, and have improvedpotency in the whole blood BCR-stimulated CD₆₉ expression assay. Thesecompounds are provided to be useful as pharmaceuticals with desirablestability, bioavailability, therapeutic index, and toxicity values thatare important to their drugability.

SUMMARY OF THE INVENTION

The present invention provides substituted tetrahydrocarbazole andcarbazole compounds, which are useful as inhibitors of Btk, and areuseful for the treatment of proliferative diseases, allergic diseases,autoimmune diseases and inflammatory diseases, including prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising at least one compound of Formula (I) and a pharmaceuticallyacceptable carrier.

The present invention also provides a method of inhibiting Btk activitycomprising administering to a mammal in need thereof at least onecompound of Formula (I).

The present invention also provides a method for treating allergicdisorders and/or autoimmune and/or inflammatory diseases, comprisingadministering to a mammal in need thereof at least one compound ofFormula (I).

The present invention also provides a method for treating proliferativediseases, such as cancer, comprising administering to a mammal in needthereof at least one compound of Formula (I).

The present invention also provides a method of treating a disease ordisorder associated with Btk activity, the method comprisingadministering to a mammal in need thereof, at least one compound ofFormula (I).

The present invention also provides processes and intermediates formaking the compounds of Formula (I).

The present invention also provides a compound of Formula (I) for use intherapy.

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for the treatment or prophylaxisof Btk related conditions, such as proliferative diseases, allergicdiseases, autoimmune diseases and inflammatory diseases.

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for treatment of cancer.

The compounds of Formula (I) and compositions comprising the compoundsof Formula (I) may be used in treating, preventing, or curing variousBtk related conditions. Pharmaceutical compositions comprising thesecompounds are useful in treating, preventing, or slowing the progressionof diseases or disorders in a variety of therapeutic areas, such asproliferative diseases, allergic diseases, autoimmune diseases andinflammatory diseases.

These and other features of the invention will be set forth in expandedform as the disclosure continues.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by reference to the accompanying drawingsdescribed below.

FIG. 1 shows the absolute stereochemistry of Intermediate 30 diaceticacid solvate.

FIG. 2 shows the absolute stereochemistry of Intermediate 35.

FIG. 3 shows the absolute stereochemistry of Example 2 methanolate,crystal Form M-1.

FIG. 4 shows the absolute stereochemistry of Example 11 methanolate,crystal Form M-1.

FIG. 5 shows the absolute stereochemistry of Example 28 dimethanolate,crystal Form M2-1.

FIG. 6 shows the absolute stereochemistry of Example 33 dimethanolate,crystal Form M2-1.

FIG. 7 shows the experimental and the simulated PXRD patterns at roomtemperature (Cu Kα radiation λ=1.5418 Å) of Example 11 monohydrate,crystal Form H-1.

FIG. 8 shows the simulated PXRD pattern at room temperature (Cu Kαradiation λ=1.5418 Å) of the crystal Form N-2 of Example 11.

FIG. 9 shows the experimental and the simulated PXRD patterns at roomtemperature (Cu Kα radiation λ=1.5418 Å) of Example 11 methanolate,crystal Form M-1.

FIG. 10 shows the simulated PXRD pattern at 173 K(Cu Kα radiationλ=1.5418 Å) of Example 28 dimethanolate, crystal Form M2-1.

FIG. 11 shows the experimental PXRD pattern at room temperature and thesimulated PXRD pattern at 173 K (Cu Kα radiation λ=1.5418 Å) of Example33 dimethanolate, crystal Form M2-1.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

wherein:the two dotted lines represent either two single or two double bonds;

Q is:

R₁ is F, Cl, —CN, or —CH₃;R₂ is Cl or —CH₃;R₃ is —C(CH₃)₂OH or —CH₂CH₂OH;R_(a) is H or —CH₃;each R_(b) is independently F, Cl, —CH₃, and/or —OCH₃; andn is zero, 1, or 2.

Atropisomers are stereoisomers resulting from hindered rotation about asingle bond axis where the rotational barrier is high enough to allowfor the isolation of the individual rotational isomers. (LaPlante etal., J. Med. Chem., 54:7005-7022 (2011).)

The compounds of Formula (A):

have two stereogenic axes: bond (a) between the tricyclictetrahydrocarbazole/carbazole group and the phenyl group; and bond (b)between the asymmetric heterocyclic dione group Q and the phenyl group.Due to the non-symmetric nature of the substitutions on the ringsconnected by the single bonds labeled a and b, and due to limitedrotation about these bonds caused by steric hindrance, the compounds ofFormula (A) can form rotational isomers. If the rotational energybarriers are sufficiently high, hindered rotations about bond (a) and/orbond (b) occur at rates that are slow enough to allow isolation of theseparated atropisomers as different compounds. Thus, the compounds ofFormula (A) can form four rotational isomers, which under certainconditions, such as chromatography on a chiral stationary phase, can beseparated into individual atropisomers. In solution, the compounds ofFormula (A) can be provided as a mixture of four diastereomers, ormixtures of two pairs of diastereomers, or single atropisomers.

For the compounds of Formula (A), the pair of rotational isomers formedby hindered rotation about stereogenic axis (a) can be represented bythe compounds of Formula (I) and Formula (B) having the structures:

The compounds of Formula (I) and the compounds of Formula (B) were foundto be separable and stable in solution at ambient and physiologicaltemperatures. Additionally, rotational isomers are formed by hinderedrotation about stereogenic axis (b). These two atropisomers of thecompounds of Formula (I) were also found to be separable and stable insolution at ambient and physiological temperatures.

Chiral compounds, such as the compounds of Formula (A), can be separatedby various techniques including Supercritical Fluid Chromatography(SFC). SFC, which is a form of normal phase HPLC, is a separationtechnique that uses super/subcritical fluid CO₂ and polar organicmodifiers such as alcohols as mobile phases. (White et al., J.Chromatography A, 1074:175-185 (2005).)

The compounds of Formula (I) wherein Q is

can be represented by the structure of Formula (II):

The four rotational isomers of the compound of Formula (A) wherein Q is

can be represented by compounds of Formula (II) having the structures ofFormula (II-1) and (II-2):

and the compounds of Formula (B) having the structures of Formula (B-1)and (B-2):

The compounds of Formula (I) wherein Q is

can be represented by the structure of Formula (III):

The four rotational isomers of the compound of Formula (A) wherein Q is

can be represented by the compounds of Formula (III) having thestructures of Formula (III-1) and (III-2):

and the compounds of Formula (B) having the structures of Formula (B-3)and (B-4):

The compounds of Formula (I) wherein Q is

can be represented by the structure of Formula (IV):

The four rotational isomers of the compound of Formula (A) wherein Q is

can be represented by the compounds of Formula (IV) having thestructures of Formula (IV-1) and (IV-2):

and the compounds of Formula (B) having the structures of Formula (B-5)and (B-6):

The compounds of Formula (I) wherein Q is

can be represented by the structure of Formula (V):

The four rotational isomers of the compound of Formula (A) wherein Q is

can be represented by the compounds of Formula (V), having thestructures of Formula (V-1) and (V-2):

and the compounds of Formula (B) having the structures of Formula (B-7)and (B-8):

The absolute spacial configurations of the atropisomers can bedetermined by single crystal x-ray crystallography.

The compounds of Formula (I) can be provided as individual atropisomersor as mixtures comprising the two atropisomers of Formula (I) in anyproportions. The mixture of the two atropisomers of Formula (I) mayoptionally contain one or both atropisomers of Formula (B) in anyproportions.

The compounds of Formula (I) in which R₁ is F, Cl, or —CH₃ correspond tothe (R)-atropisomer with respect to the stereogenic axis formed by bond(a). The compounds of Formula (B) in which R₁ is F, Cl, or —CH₃correspond to the (S)-atropisomer with respect to the stereogenic axisformed by bond (a).

The compounds of Formula (I) in which R₁ is —CN correspond to the(S)-atropisomer with respect to the stereogenic axis formed by bond (a).The compounds of Formula (B) in which R₁ is —CN correspond to the(R)-atropisomer with respect to the stereogenic axis formed by bond (a).

As used herein, the phase “the two dotted lines represent either twosingle or two double bonds” refers to compounds of Formula (A), (B),(I), (II), (III), (IV), and (V) in which the two dotted lines aresimultaneously single bonds or the two dotted lines are simultaneouslydouble bonds. For example, the compounds of Formula (I) in which the twodotted lines are simultaneously single bonds are tetrahydrocarbazolecompounds having the structure of Formula (IA) and the compounds ofFormula (I) in which the two dotted lines are simultaneously doublebonds are carbazole compounds having the structure of Formula (IB):

The tetrahydrocarbazole compounds represented by Formula (IA) also havea chiral center at the carbon atom to which the substituent R³ isattached, and thus can exist as S- and R-isomers at this chiral center.

These isomers are separable and are stable. One embodiment providescompounds of Formula (IA) with the carbon chiral center to which the R³substituent is attached, as the S-isomer. One embodiment provides thecompounds of Formula (IA) with the carbon chiral center to which the R³substituent is attached, as the R-isomer.

One embodiment provides compounds of Formula (I) wherein R₃ is—C(CH₃)₂OH; and R₁, R₂, and Q are defined in the first aspect. Includedin this embodiment are compounds in which Q is:

and R_(a), R_(b), and n are defined in the first aspect. Also includedin this embodiment are compounds of Formula (IA). Other compoundsincluded in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (II) wherein R₃ is—C(CH₃)₂OH; and R₁, R₂, R_(a), R_(b), and n are defined in the firstaspect. Included in this embodiment are compounds in which in whichR_(a) is —CH₃ including -CD₃.

One embodiment provides compounds of Formula (III) wherein R₃ is—C(CH₃)₂OH; and R₁, R₂, R_(b), and n are defined in the first aspect.Included in this embodiment are compounds in which in which each R_(b)is independently F or Cl.

One embodiment provides compounds of Formula (IV) wherein R₃ is—C(CH₃)₂OH; and R₁ and R₂ are defined in the first aspect. Included inthis embodiment are compounds in which R₁ is F, Cl, or —CH₃.

One embodiment provides compounds of Formula (V) wherein R₃ is—C(CH₃)₂OH; and R₁ and R₂ are defined in the first aspect. Included inthis embodiment are compounds in which R₁ is F, Cl, or —CH₃.

One embodiment provides compounds of Formula (I) wherein R₁ is F.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is Cl.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is F or Cl.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is —CH₃.

Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is —CN.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is F, Cl, or—CN. Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is —CH₃ or—CN. Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₁ is F, Cl, or—CH₃. Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (I) wherein R₂ is Cl.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).Also, included in this embodiment are compounds in which R₃ is—C(CH₃)₂OH.

One embodiment provides compounds of Formula (I) wherein R₂ is —CH₃.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).Also, included in this embodiment are compounds in which R₃ is—C(CH₃)₂OH.

One embodiment provides compounds of Formula (I) wherein R₃ is—C(CH₃)₂OH. Included in this embodiment are compounds of Formula (IA).Other compounds included in this embodiment are the compounds of Formula(M).

One embodiment provides compounds of Formula (I) wherein each R_(b) isindependently F and/or Cl. Included in this embodiment are compounds inwhich n is 1 or 2. Also included in this embodiment are compounds inwhich n is 2 and each R_(b) is F.

One embodiment provides compounds of Formula (I) wherein n is 1 andR_(b) is —CH₃ or —OCH₃.

One embodiment provides compounds of Formula (I) wherein n is zero.Included in this embodiment are compounds of Formula (IA). Othercompounds included in this embodiment are the compounds of Formula (IB).

One embodiment provides compounds of Formula (II) in which the twodotted lines are simultaneously single bonds and R₁, R₂, R₃, R_(a),R_(b), and n are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (IIA):

The two rotational isomers of the compound of Formula (IIA) arerepresented by the structures of Formula (IIA-1) and (IIA-2):

Included in this embodiment are compounds of Formula (IIA), (IIA-1), and(IIA-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (II) in which the twodotted lines are simultaneously double bonds and R₁, R₂, R₃, R_(a),R_(b), and n are defined in the first aspect. Compounds of thisembodiment have the structure of Formula (IIB):

The two rotational isomers of the compound of Formula (IIB) arerepresented by the structures of Formula (IIB-1) and (IIB-2):

Included in this embodiment are compounds of Formula (IIB), (IIB-1), and(IIB-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (II) wherein R_(a) is H.Included in this embodiment are compounds of Formula (IIA). Othercompounds included in this embodiment are the compounds of Formula(IIB).

One embodiment provides compounds of Formula (II) wherein R_(a) is —CH₃.

Included in this embodiment are compounds in which R_(a) is -CD₃. Also,included in this embodiment are compounds of Formula (IIA). Othercompounds included in this embodiment are the compounds of Formula(IIB).

One embodiment provides compounds of Formula (III) in which the twodotted lines are simultaneously single bonds and R₁, R₂, R₃, R_(b), andn are defined in the first aspect. Compounds of this embodiment have thestructure of Formula (IIIA):

The two rotational isomers of the compound of Formula (IIIA) arerepresented by the structures of Formula (IIIA-1) and (IIIA-2):

Included in this embodiment are compounds of Formula (IIIA), (IIIA-1),and (IIIA-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (III) in which the twodotted lines are simultaneously double bonds and R₁, R₂, R₃, R_(b), andn are defined in the first aspect. Compounds of this embodiment have thestructure of Formula (IIIB):

The two rotational isomers of the compound of Formula (IIIB) arerepresented by the structures of Formula (IIIB-1) and (IIIB-2):

Included in this embodiment are compounds of Formula (IIIB), (IIIB-1),and (IIIB-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (IV) in which the twodotted lines are simultaneously single bonds and R₁, R₂, and R₃ aredefined in the first aspect. Compounds of this embodiment have thestructure of Formula (IVA):

The two rotational isomers of the compound of Formula (IVA) arerepresented by the structures of Formula (IVA-1) and (IVA-2):

Included in this embodiment are compounds of Formula (IVA), (IVA-1), and(IVA-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (IV) in which the twodotted lines are simultaneously double bonds and R₁, R₂, and R₃ aredefined in the first aspect. Compounds of this embodiment have thestructure of Formula (IVB):

The two rotational isomers of the compound of Formula (IVB) arerepresented by the structures of Formula (IVB-1) and (IVB-2):

Included in this embodiment are compounds of Formula (IVB), (IVB-1), and(IVB-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (V) in which the two dottedlines are simultaneously single bonds and R₁, R₂, and R₃ are defined inthe first aspect. Compounds of this embodiment have the structure ofFormula (VA):

The two rotational isomers of the compound of Formula (VA) arerepresented by the structures of Formula (VA-1) and (VA-2):

Included in this embodiment are compounds of Formula (VA), (VA-1), and(VA-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides compounds of Formula (V) in which the two dottedlines are simultaneously double bonds and R₁, R₂, and R₃ are defined inthe first aspect. Compounds of this embodiment have the structure ofFormula (VB):

The two rotational isomers of the compound of Formula (VB) arerepresented by the structures of Formula (VB-1) and (VB-2):

Included in this embodiment are compounds of Formula (VB), (VB-1), and(VB-2) in which R₃ is —C(CH₃)₂OH.

One embodiment provides a compound of Formula (I) having the structure:

wherein R₁ is Cl or F; and R_(a) is —CH₃ including -CD₃.

One embodiment provides a compound of Formula (I) having the structure:

wherein R₁ is Cl or F; and R_(a) is —CH₃ including -CD₃.

One embodiment provides a compound of Formula (I) having the structure:

wherein R₁ is Cl or F; and R_(a) is —CH₃ including -CD₃.

One embodiment provides a compound of Formula (I) having the structure:

One embodiment provides a compound of Formula (I) or having thestructure:

One embodiment provides a compound of Formula (I) having the structure:

One embodiment provides a compound selected from the exemplifiedexamples within the scope of the first aspect.

One embodiment provides a compound selected from any subset list ofcompounds within the scope of the first aspect or of any of the aboveembodiments.

One embodiment provides a compound of Formula (II) wherein the compoundis:3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(1);3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(2);3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide(3);3-chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(4);3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(R)-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(5);3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(S)-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(6);3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(7);3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(8);3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(9);3-chloro-4-(R)-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(10);3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(11);3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(12);3-chloro-4-(R)-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(13);3-chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(14);3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(15 and 16);3-fluoro-4-(R)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(17);3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(18);3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(19);3-fluoro-4-(R)-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(20);3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(21);3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(22);6-chloro-5-(R)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(25);6-chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(26);6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(27);6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(28);4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide(29);3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(42);3-chloro-4-(R)-(2-chloro-3-(R)-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(43);3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(44);3-chloro-4-(R)-(2-chloro-3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(45);4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(46);3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(47);

One embodiment provides a compound of Formula (III) wherein the compoundis:3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(23);4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(30 and 31);3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(32);3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(33);3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(34);3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(35 and 36);3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(37);3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(40 and 41);

One embodiment provides a compound of Formula (IV) wherein the compoundis:3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(38 and 39).

One embodiment provides a compound of Formula (V) wherein the compoundis:3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(24).

In one embodiment, a composition is provided comprising a compound ofFormula (I). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (I) and (ii) acompound of Formula (B).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (I), based on the totalequivalent weight of the compound of Formula (I) and its atropisomercompound of Formula (B). Included in this embodiment, are compositionscomprising at 99 equivalent weight %, 99.5 equivalent weight %, 99.8equivalent weight %, and 99.9 equivalent weight % of a compound ofFormula (I) based on the total equivalent weight of the compound ofFormula (I) and its atropisomer compound of Formula (B). Compositions ofthis embodiment include pharmaceutical compositions.

In one embodiment, a composition is provided comprising a compound ofFormula (II). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (II) and (ii) oneor both of its atropisomer compounds of Formula (B-1) and (B-2).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (II), based on the totalequivalent weight of the compound of Formula (II) and its atropisomercompounds of Formula (B-1) and (B-2). Included in this embodiment, arecompositions comprising at 99 equivalent weight %, 99.5 equivalentweight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of acompound of Formula (II) based on the total equivalent weight of thecompound of Formula (II) and its atropisomer compounds of Formula (B-1)and (B-2). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (III). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (III) and (ii)one or both of its atropisomer compounds of Formula (B-3) and (B-4).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (III), based on the totalequivalent weight of the compound of Formula (III) and its atropisomercompounds of Formula (B-3) and (B-4). Included in this embodiment, arecompositions comprising at 99 equivalent weight %, 99.5 equivalentweight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of acompound of Formula (III) based on the total equivalent weight of thecompound of Formula (III) and its atropisomer compounds of Formula (B-3)and (B-4). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (IV). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (IV) and (ii) oneor both of its atropisomer compounds of Formula (B-5) and (B-6).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (IV), based on the totalequivalent weight of the compound of Formula (IV) and its atropisomercompounds of Formula (B-5) and (B-6). Included in this embodiment, arecompositions comprising at 99 equivalent weight %, 99.5 equivalentweight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of acompound of Formula (IV) based on the total equivalent weight of thecompound of Formula (IV) and its atropisomer compounds of Formula (B-5)and (B-6). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (V). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (V) and (ii) oneor both of its atropisomer compounds of Formula (B-7) and (B-8).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (V), based on the totalequivalent weight of the compound of Formula (V) and its atropisomercompounds of Formula (B-7) and (B-8). Included in this embodiment, arecompositions comprising at 99 equivalent weight %, 99.5 equivalentweight %, 99.8 equivalent weight %, and 99.9 equivalent weight % of acompound of Formula (V) based on the total equivalent weight of thecompound of Formula (V) and its atropisomer compounds of Formula (B-7)and (B-8). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (II-1). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (II-1) and (ii)one or more of its atropisomer compounds of Formula (II-2), Formula(B-1) and (B-2).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (II-1), based on the totalequivalent weight of the compounds of Formula (II-1), (II-2), (B-1), and(B-2). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (II-1) based onthe total equivalent weight of the compounds of Formula (II-1), (II-2),(B-1), and (B-2). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (II-2). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (II-2) and (ii)one or more of its atropisomer compounds of Formula (II-1), Formula(B-1) and (B-2).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (II-2), based on the totalequivalent weight of the compounds of Formula (II-1), (II-2), (B-1), and(B-2). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (II-2) based onthe total equivalent weight of the compounds of Formula (II-1), (II-2),(B-1), and (B-2). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (III-1). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (III-1) and(ii) one or more of its atropisomer compounds of Formula (III-2),Formula (B-3) and (B-4).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (III-1), based on the totalequivalent weight of the compounds of Formula (III-1), (III-2), (B-3),and (B-4). Included in this embodiment, are compositions comprising at99 equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight%, and 99.9 equivalent weight % of a compound of Formula (III-1) basedon the total equivalent weight of the compounds of Formula (III-1),(III-2), (B-3), and (B-4). Compositions of this embodiment includepharmaceutical compositions.

In one embodiment, a composition is provided comprising a compound ofFormula (III-2). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (III-2) and(ii) one or more of its atropisomer compounds of Formula (III-1),Formula (B-3) and (B-4).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (III-2), based on the totalequivalent weight of the compounds of Formula (III-1), (III-2), (B-3),and (B-4). Included in this embodiment, are compositions comprising at99 equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight%, and 99.9 equivalent weight % of a compound of Formula (III-2) basedon the total equivalent weight of the compounds of Formula (III-1),(III-2), (B-3), and (B-4). Compositions of this embodiment includepharmaceutical compositions.

In one embodiment, a composition is provided comprising a compound ofFormula (IV-1). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (IV-1) and (ii)one or more of its atropisomer compounds of Formula (IV-2), Formula(B-5) and (B-6).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (IV-1), based on the totalequivalent weight of the compounds of Formula (IV-1), (IV-2), (B-5), and(B-6). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (IV-1) based onthe total equivalent weight of the compounds of Formula (IV-1), (IV-2),(B-5), and (B-6). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (IV-2). Included in this embodiment is a composition comprisinga mixture in any proportion of (i) a compound of Formula (IV-2) and (ii)one or more of its atropisomer compounds of Formula (IV-1), Formula(B-5) and (B-6).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (IV-2), based on the totalequivalent weight of the compounds of Formula (IV-1), (IV-2), (B-5), and(B-6). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (IV-2) based onthe total equivalent weight of the compounds of Formula (IV-1), (IV-2),(B-5), and (B-6). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (V-1). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (V-1) and (ii)one or more of its atropisomer compounds of Formula (V-2), Formula (B-7)and (B-8).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (V-1), based on the totalequivalent weight of the compounds of Formula (V-1), (V-2), (B-7), and(B-8). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (V-1) based on thetotal equivalent weight of the compounds of Formula (V-1), (V-2), (B-7),and (B-8). Compositions of this embodiment include pharmaceuticalcompositions.

In one embodiment, a composition is provided comprising a compound ofFormula (V-2). Included in this embodiment is a composition comprising amixture in any proportion of (i) a compound of Formula (V-2) and (ii)one or more of its atropisomer compounds of Formula (V-1), Formula (B-7)and (B-8).

In one embodiment, a composition is provided comprising at least 98equivalent weight % of a compound of Formula (V-2), based on the totalequivalent weight of the compounds of Formula (V-1), (V-2), (B-7), and(B-8). Included in this embodiment, are compositions comprising at 99equivalent weight %, 99.5 equivalent weight %, 99.8 equivalent weight %,and 99.9 equivalent weight % of a compound of Formula (V-2) based on thetotal equivalent weight of the compounds of Formula (V-1), (V-2), (B-7),and (B-8). Compositions of this embodiment include pharmaceuticalcompositions.

Crystal Forms

TABLE 1 Example Form 2 M-1 11 H-1 11 N-2 11 M-1 28 M2-1 33 M2-1

In one embodiment, the compound of Example 2 is provided as acrystalline material comprising Form M-1. This crystalline form of thecompound of Example 2 comprises a methanol solvate crystalline formreferred to herein as “Form M-1” or “M-1 Form” of Example 2. The M-1Form of Example 2 comprises one molecule of methanol for each moleculeof Example 2.

In one embodiment, the M-1 Form of the compound of Example 2 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=9.75 Å    -   b=14.21 Å    -   c=21.26 Å    -   α=90.0°    -   β=90.0°    -   γ=90.0°

Space group: P2₁2₁2₁

Molecules of Example 2/asymmetric unit: 1

Volume/Number of molecules in the unit cell=736 Å³

Density (calculated)=1.391 g/cm³,

wherein the unit cell parameters of Form M-1 are measured at atemperature of about 203 K.

In yet an even further embodiment, the M-1 Form of Example 2 ischaracterized by fractional atomic coordinates substantially as listedin Table 2.

TABLE 2 Fractional Atomic Coordinates of Example 2, Form M-1 Calculatedat a Temperature of about 203 K; Atomic Coordinates (x104) Atom X Y ZCl1 0.5111 0.2098 0.2452 N1 0.4284 −0.0941 0.0651 C1 0.4089 0.04020.2141 C2 0.4430 −0.0331 0.1143 C3 0.5134 −0.0987 −0.0462 C4 0.53110.0412 0.0962 C5 0.5042 −0.0618 0.0142 C6 0.3830 −0.0362 0.1748 C70.6528 0.0676 −0.0127 C8 0.4911 0.1146 0.1945 C9 0.5570 0.1167 0.1365C10 0.5928 −0.0859 −0.1587 C11 0.5718 0.0218 0.0316 C12 0.5929 −0.0521−0.0902 C13 0.6628 0.0308 −0.0728 O1 0.5612 −0.1842 −0.1607 C14 0.4745−0.0373 −0.1922 C15 0.2943 −0.1171 0.1922 C16 0.7270 −0.0662 −0.1926 O20.2647 −0.1777 0.1522 N2 0.2483 −0.1213 0.2514 C17 0.6935 0.3440 0.0689C18 0.8335 0.3314 0.0747 C19 0.6506 0.1944 0.1165 C20 0.5982 0.27690.0896 C21 0.8827 0.2492 0.1010 C22 0.7908 0.1819 0.1221 C23 0.44700.2921 0.0824 N3 0.6425 0.4284 0.0392 C24 0.6079 0.5032 0.0785 N4 0.54490.5793 0.0505 C25 0.5043 0.5772 −0.0128 C26 0.6347 0.4289 −0.0265 C270.3810 0.6409 −0.1018 C28 0.5564 0.5079 −0.0530 C29 0.5260 0.5081−0.1169 C30 0.4122 0.6409 −0.0392 C31 0.4401 0.5750 −0.1415 O3 0.68260.3654 −0.0574 O4 0.6337 0.5004 0.1344 C32 0.5414 0.6667 0.0876 F10.3478 0.7048 −0.0014 O5 0.4744 −0.2738 −0.2654 C33 0.3392 −0.2608−0.2825 H1 0.3792 −0.1452 0.0656 H2 0.3702 0.0415 0.2546 H3 0.4665−0.1543 −0.0570 H4 0.7002 0.1230 −0.0020 H5 0.7175 0.0617 −0.1027 H60.6298 −0.2150 −0.1502 H7 0.4710 −0.0582 −0.2356 H8 0.4881 0.0302−0.1910 H9 0.3890 −0.0531 −0.1713 H10 0.8030 −0.0882 −0.1671 H11 0.73610.0009 −0.1996 H12 0.7275 −0.0988 −0.2327 H13 0.1959 −0.1676 0.2631 H140.2709 −0.0777 0.2782 H15 0.8945 0.3782 0.0608 H16 0.9776 0.2391 0.1046H17 0.8245 0.1265 0.1406 H18 0.3989 0.2335 0.0902 H19 0.4275 0.31350.0399 H20 0.4165 0.3393 0.1122 H21 0.3195 0.6857 −0.1180 H22 0.56460.4622 −0.1434 H23 0.4213 0.5761 −0.1848 H24 0.4485 0.6782 0.1021 H250.5711 0.7190 0.0615 H26 0.6021 0.6608 0.1234 H27 0.4880 −0.2496 −0.2304H28 0.2809 −0.3001 −0.2565 H29 0.3273 −0.2780 −0.3263 H30 0.3142 −0.1953−0.2767

In one embodiment, the compound of Example 11 is provided as acrystalline material comprising Form H-1. This crystalline form of thecompound of Example 11 comprises a monohydrate crystalline form referredto herein as “Form H-1” or “H-1 Form” of Example 11. The H-1 Form ofExample 11 comprises one molecule of water for each molecule of Example11.

In one embodiment, the H-1 Form of the compound of Example 11 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=9.41 Å    -   b=14.51 Å    -   c=21.12 Å    -   α=90.0°    -   β=90.0°    -   γ=90.0°

Space group: P2₁2₁2₁

Molecules of Example 11/asymmetric unit: 1

Volume/Number of molecules in the unit cell=721 Å³

Density (calculated)=1.396 g/cm³,

wherein the unit cell parameters of Form H-1 are measured at atemperature of about room temperature.

In another embodiment, H-1 form of Example 11 is characterized by asimulated powder x-ray diffraction (PXRD) pattern substantially inaccordance with the pattern shown in FIG. 7 and/or by an experimentalPXRD pattern substantially in accordance with the pattern shown in FIG.7.

In yet an even further embodiment, the H-1 Form of Example 11 ischaracterized by fractional atomic coordinates substantially as listedin Table 3.

TABLE 3 Fractional Atomic Coordinates of Example 11, Form H-1 Calculatedat Room Temperature; Atomic Coordinates (x10⁴) Atom X Y Z Cl1 0.47830.2052 0.2387 N1 0.4348 −0.0990 0.0600 C1 0.4427 −0.0381 0.1093 C20.3961 0.0338 0.2082 C3 0.5280 0.0384 0.0908 C4 0.5215 −0.0998 −0.0525C5 0.3806 −0.0431 0.1694 C6 0.6503 0.0680 −0.0190 C7 0.5093 −0.06480.0087 C8 0.5466 0.1131 0.1314 C9 0.4735 0.1097 0.1887 C10 0.5719 0.02010.0261 C11 0.6615 0.0322 −0.0793 C12 0.5970 −0.0514 −0.0970 C13 0.5968−0.0824 −0.1662 O1 0.5643 −0.1789 −0.1705 C14 0.7370 −0.0628 −0.1994 C150.4767 −0.0343 −0.1997 C16 0.3010 −0.1271 0.1879 O2 0.2749 −0.18740.1484 N2 0.2591 −0.1344 0.2483 C17 0.6425 0.1917 0.1143 C18 0.68630.3413 0.0723 C19 0.7866 0.1827 0.1254 C20 0.8297 0.3327 0.0837 C210.8807 0.2530 0.1104 C22 0.5887 0.2724 0.0870 C23 0.4341 0.2839 0.0745N3 0.6351 0.4252 0.0428 C24 0.6028 0.4987 0.0826 N4 0.5451 0.5756 0.0548C25 0.5048 0.5763 −0.0091 C26 0.5515 0.5068 −0.0496 C27 0.6265 0.4268−0.0234 C28 0.5218 0.5088 −0.1139 C29 0.4158 0.6426 −0.0357 C30 0.38480.6446 −0.0985 C31 0.4396 0.5789 −0.1388 O3 0.6707 0.3631 −0.0545 O40.6282 0.4945 0.1389 C32 0.5492 0.6607 0.0922 D1 0.4548 0.6763 0.1057 D20.5866 0.7098 0.0666 D3 0.6089 0.6519 0.1285 F1 0.3543 0.7073 0.0021 O50.3852 −0.2732 −0.2607 H1 0.3903 −0.1507 0.0608 H2 0.3536 0.0342 0.2480H3 0.4788 −0.1556 −0.0631 H4 0.6945 0.1233 −0.0086 H5 0.7136 0.0645−0.1094 H6 0.6241 −0.2085 −0.1509 H7 0.8132 −0.0904 −0.1760 H8 0.75140.0026 −0.2019 H9 0.7344 −0.0882 −0.2414 H10 0.4742 −0.0535 −0.2431 H110.4909 0.0312 −0.1976 H12 0.3885 −0.0499 −0.1795 H13 0.2127 −0.18220.2605 H14 0.2789 −0.0913 0.2748 H15 0.8211 0.1285 0.1433 H16 0.89150.3806 0.0735 H17 0.9774 0.2462 0.1183 H18 0.3940 0.3251 0.1052 H190.3878 0.2250 0.0774 H20 0.4206 0.3088 0.0328 H21 0.5571 0.4629 −0.1402H22 0.3260 0.6907 −0.1143 H23 0.4216 0.5818 −0.1821 H24 0.4426 −0.2428−0.2322 H25 0.2940 −0.2508 −0.2576 — — — —

In one embodiment, the compound of Example 11 is provided as acrystalline material comprising Form N-2. This crystalline form of thecompound of Example 11 comprises a neat crystalline form referred toherein as “Form N-2” or “N-2 Form” of Example 11.

In one embodiment, the N-2 Form of the compound of Example 11 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=10.89 Å    -   b=9.47 Å    -   c=14.28 Å    -   α=90.0°    -   β=105.5°    -   γ=90.0°

Space group: P2₁

Molecules of Example 11/asymmetric unit: 1

Volume/Number of molecules in the unit cell=710 Å³

Density (calculated)=1.369 g/cm³,

wherein the unit cell parameters of Form N-2 are measured at atemperature of about room temperature.

In another embodiment, N-2 form of Example 11 is characterized by asimulated powder x-ray diffraction (PXRD) pattern substantially inaccordance with the pattern shown in FIG. 8.

In yet an even further embodiment, the N-2 Form of Example 11 ischaracterized by fractional atomic coordinates substantially as listedin Table 4.

TABLE 4 Fractional Atomic Coordinates of Example 11, Form N-2 Calculatedat Room Temperature; Atomic Coordinates (x10⁴) Atom X Y Z Cl1 0.01260.5814 −0.0398 N28 0.4096 0.6892 −0.1985 N1 0.3977 0.4748 0.3228 C60.2421 0.6140 0.0877 C3 0.1740 0.4291 0.2250 C4 0.0901 0.4607 0.1367 C70.3291 0.5833 0.1771 C10 0.6696 0.7241 0.2527 C8 0.4600 0.6251 0.2204 C20.2949 0.4910 0.2436 C5 0.1241 0.5497 0.0709 C11 0.7085 0.6521 0.3424C12 0.6222 0.5671 0.3708 C13 0.4986 0.5553 0.3100 C9 0.5476 0.71040.1920 C14 0.8476 0.6567 0.4037 O15 0.8564 0.6165 0.5020 C18 0.14390.3323 0.2987 C17 0.9207 0.5431 0.3663 C16 0.9095 0.7999 0.4029 O190.2223 0.3164 0.3783 N20 0.0317 0.2672 0.2766 C21 0.2745 0.7085 0.0137C22 0.3280 0.6518 −0.0566 C23 0.3515 0.7447 −0.1255 C26 0.2482 0.85160.0138 C24 0.3252 0.8854 −0.1258 C25 0.2734 0.9408 −0.0553 C27 0.35670.4978 −0.0589 C29 0.3283 0.6529 −0.2889 N30 0.3839 0.5912 −0.3541 C360.5943 0.5995 −0.2422 C31 0.5122 0.5507 −0.3280 C32 0.5654 0.4577−0.3830 C35 0.7220 0.5668 −0.2168 C37 0.5426 0.6797 −0.1732 C34 0.77170.4812 −0.2747 C33 0.6929 0.4253 −0.3569 O38 0.6061 0.7269 −0.0972 O390.2156 0.6776 −0.3073 C40 0.3090 0.5904 −0.4562 F41 0.4905 0.3950−0.4631 H1 0.3995 0.4230 0.3726 H4 0.0089 0.4214 0.1210 H10 0.72760.7822 0.2338 H12 0.6458 0.5184 0.4295 H9 0.5245 0.7578 0.1329 H150.8171 0.6734 0.5263 H17A 1.0065 0.5391 0.4070 H17B 0.9217 0.5650 0.3009H17C 0.8800 0.4535 0.3675 H16A 0.8623 0.8699 0.4274 H16B 0.9097 0.82360.3375 H16C 0.9956 0.7969 0.4432 H20A 0.0121 0.2121 0.3182 H20B −0.02120.2801 0.2206 H26 0.2130 0.8882 0.0612 H24 0.3419 0.9439 −0.1733 H250.2557 1.0368 −0.0544 H27A 0.2879 0.4513 −0.1048 H27B 0.3664 0.45810.0045 H27C 0.4341 0.4851 −0.0779 H35 0.7752 0.6032 −0.1598 H34 0.85850.4614 −0.2581 H33 0.7257 0.3648 −0.3955 D40A 0.2768 0.4970 −0.4739 D40B0.3622 0.6185 −0.4968 D40C 0.2390 0.6551 −0.4647

In one embodiment, the compound of Example 11 is provided as acrystalline material comprising Form M-1. This crystalline form of thecompound of Example 11 comprises a methanol solvate crystalline formreferred to herein as “Form M-1” or “M-1 Form” of Example 11. The M-1Form of Example 11 comprises one molecule of methanol for each moleculeof Example 11.

In one embodiment, the M-1 Form of the compound of Example 11 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=9.78 Å    -   b=14.26 Å    -   c=21.38 Å    -   α=90.0°    -   β=90.0°    -   γ=90.0°

Space group: P2₁2₁2₁

Molecules of Example 11/asymmetric unit: 1

Volume/Number of molecules in the unit cell=746 Å³

Density (calculated)=1.381 g/cm³,

wherein the unit cell parameters of Form M-1 are measured at atemperature of about room temperature.

In another embodiment, M-1 form of Example 11 is characterized by asimulated powder x-ray diffraction (PXRD) pattern substantially inaccordance with the pattern shown in FIG. 9 and/or by an experimentalPXRD pattern substantially in accordance with the pattern shown in FIG.9.

In yet an even further embodiment, the M-1 Form of Example 11 ischaracterized by fractional atomic coordinates substantially as listedin Table 5.

TABLE 5 Fractional Atomic Coordinates of Example 11, Form M-1 Calculatedat Room Temperature; Atomic Coordinates (x10⁴) Atom X Y Z Cl1 0.51220.2066 0.2450 N1 0.4273 −0.0936 0.0641 C1 0.5289 0.0415 0.0955 C2 0.5116−0.0974 −0.0464 C3 0.5023 −0.0607 0.0136 C4 0.4097 0.0384 0.2129 C50.3831 −0.0373 0.1735 C6 0.4422 −0.0331 0.1135 C7 0.5686 0.0224 0.0311C8 0.5550 0.1158 0.1358 C9 0.6496 0.0688 −0.0131 C10 0.4913 0.11250.1938 C11 0.5915 −0.0838 −0.1580 C12 0.5911 −0.0506 −0.0901 C13 0.65940.0319 −0.0724 O1 0.5610 −0.1824 −0.1606 C14 0.2956 −0.1183 0.1908 C150.4743 −0.0364 −0.1918 C16 0.7257 −0.0643 −0.1914 O2 0.2663 −0.17850.1512 N2 0.2503 −0.1229 0.2496 C17 0.6898 0.3431 0.0697 C18 0.82900.3311 0.0758 C19 0.5954 0.2757 0.0893 C20 0.6478 0.1941 0.1162 C210.7878 0.1825 0.1226 C22 0.8782 0.2501 0.1022 C23 0.4452 0.2902 0.0817N3 0.6391 0.4273 0.0400 C24 0.6052 0.5019 0.0789 N4 0.5432 0.5777 0.0514C25 0.5035 0.5761 −0.0117 C26 0.6313 0.4281 −0.0253 C27 0.5542 0.5067−0.0516 C28 0.5238 0.5074 −0.1149 C29 0.3824 0.6403 −0.1003 C30 0.41260.6400 −0.0381 C31 0.4398 0.5745 −0.1396 O3 0.6783 0.3646 −0.0559 O40.6315 0.4993 0.1345 C32 0.5414 0.6652 0.0884 D1 0.4501 0.6772 0.1028 D20.5715 0.7164 0.0628 D3 0.6014 0.6588 0.1237 F1 0.3490 0.7042 −0.0007 O50.4716 −0.2733 −0.2643 C33 0.3374 −0.2588 −0.2808 H1 0.3791 −0.14400.0644 H2 0.4656 −0.1521 −0.0572 H3 0.3719 0.0392 0.2528 H4 0.69600.1235 −0.0027 H5 0.7131 0.0626 −0.1019 H6 0.6289 −0.2124 −0.1504 H70.4747 −0.0549 −0.2350 H8 0.4845 0.0304 −0.1890 H9 0.3894 −0.0547−0.1729 H10 0.8000 −0.0891 −0.1672 H11 0.7373 0.0021 −0.1964 H12 0.7247−0.0938 −0.2318 H13 0.1990 −0.1687 0.2610 H14 0.2724 −0.0800 0.2760 H150.8889 0.3773 0.0621 H16 0.8214 0.1281 0.1410 H17 0.9719 0.2410 0.1065H18 0.4004 0.2305 0.0788 H19 0.4283 0.3257 0.0444 H20 0.4104 0.32380.1173 H21 0.5610 0.4617 −0.1409 H22 0.3229 0.6851 −0.1163 H23 0.42150.5757 −0.1823 H24 0.4869 −0.2481 −0.2306 H25 0.3304 −0.2025 −0.3052 H260.2828 −0.2527 −0.2437 H27 0.3053 −0.3110 −0.3050

In one embodiment, the compound of Example 28 is provided as acrystalline material comprising Form M2-1. This crystalline form of thecompound of Example 28 comprises a methanol solvate crystalline formreferred to herein as “Form M2-1” or “M2-1 Form” of Example 28. The M2-1Form of Example 28 comprises two molecules of methanol for each moleculeof Example 28.

In one embodiment, the M2-1 Form of the compound of Example 28 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=9.24 Å    -   b=7.97 Å    -   c=22.12 Å    -   α=90.0°    -   β=94.1°    -   γ=90.0°

Space group: P2₁

Molecules of Example 28/asymmetric unit: 1

Volume/Number of molecules in the unit cell=813 Å³

Density (calculated)=1.301 g/cm³,

wherein the unit cell parameters of Form M2-1 are measured at atemperature of about 173 K.

In another embodiment, M2-1 form of Example 28 is characterized by asimulated powder x-ray diffraction (PXRD) pattern substantially inaccordance with the pattern shown in FIG. 10.

In yet an even further embodiment, the M2-1 Form of Example 28 ischaracterized by fractional atomic coordinates substantially as listedin Table 6.

TABLE 6 Fractional Atomic Coordinates of Example 28, Form M2-1Calculated at a Temperature of about 173 K; Atomic Coordinates (x10⁴)Atom X Y Z N1 0.1027 0.4043 0.3748 C1 −0.2232 0.3960 0.2673 C2 0.04040.5638 0.2929 C3 −0.0029 0.4268 0.3288 C4 −0.0521 0.6188 0.2437 C5−0.1336 0.3399 0.3162 C6 −0.1814 0.5329 0.2339 C7 0.5794 0.6873 0.4355C8 0.1792 0.6199 0.3196 C9 0.3425 0.5311 0.4117 C10 0.4312 0.7276 0.3333C11 0.4282 0.6926 0.4013 C12 0.2800 0.7581 0.3027 C13 0.2107 0.52210.3691 O1 0.6379 0.8543 0.4304 C14 −0.1722 0.2005 0.3567 C15 0.56880.6482 0.5022 C16 0.6824 0.5649 0.4077 O2 −0.0922 0.1697 0.4030 N2−0.2929 0.1124 0.3427 C17 0.0680 1.0435 0.1406 C18 −0.0136 0.7640 0.2053C19 −0.0685 0.9224 0.2173 C20 0.0824 0.7434 0.1594 C21 −0.0291 1.06130.1851 C22 0.1220 0.8874 0.1288 C23 0.1432 0.5751 0.1445 N3 0.23350.8729 0.0858 C24 0.3767 0.8784 0.1096 C25 0.4864 0.8571 0.0663 N40.2979 0.8380 −0.0149 C26 0.4453 0.8370 0.0049 C27 0.6314 0.8568 0.0885C28 0.5591 0.8157 −0.0330 C29 0.7023 0.8160 −0.0107 C30 0.1898 0.85200.0243 C31 0.7397 0.8355 0.0497 O3 0.4038 0.8977 0.1639 O4 0.0618 0.84820.0081 C32 0.2483 0.8261 −0.0793 F1 −0.2771 0.5872 0.1879 F2 0.53240.7902 −0.0930 O5 −0.0788 −0.0991 0.4776 C33 0.0326 −0.1899 0.4513 O60.4799 1.1498 0.2473 C34 0.3561 1.2372 0.2578 H1 0.1019 0.3275 0.4033 H2−0.3127 0.3410 0.2567 H3 0.4049 0.4324 0.4058 H4 0.3136 0.5287 0.4540 H50.4925 0.8272 0.3274 H6 0.4759 0.6309 0.3137 H7 0.3737 0.7870 0.4190 H80.2426 0.8676 0.3159 H9 0.2850 0.7612 0.2582 H10 0.7202 0.8591 0.4490H11 0.6640 0.6644 0.5240 H12 0.5377 0.5317 0.5067 H13 0.4979 0.72360.5189 H14 0.7009 0.6021 0.3668 H15 0.6384 0.4529 0.4058 H16 0.77420.5607 0.4329 H17 −0.3176 0.0302 0.3664 H18 −0.3477 0.1365 0.3097 H190.0970 1.1384 0.1185 H20 −0.1342 0.9351 0.2480 H21 −0.0683 1.1683 0.1933H22 0.1200 0.5506 0.1014 H23 0.1005 0.4889 0.1693 H24 0.2488 0.57610.1530 H25 0.6555 0.8714 0.1307 H26 0.7765 0.8024 −0.0380 H27 0.83870.8345 0.0646 H28 0.2762 0.7168 −0.0952 H29 0.2933 0.9156 −0.1019 H300.1425 0.8377 −0.0839 H31 −0.0943 −0.0091 0.4585 H32 0.1274 −0.14800.4674 H33 0.0232 −0.1756 0.4072 H34 0.0242 −0.3092 0.4612 H35 0.45971.0733 0.2219 H36 0.3799 1.3281 0.2866 H37 0.2857 1.1614 0.2746 H380.3141 1.2845 0.2195

In one embodiment, the compound of Example 33 is provided as acrystalline material comprising Form M2-1. This crystalline form of thecompound of Example 33 comprises a methanol solvate crystalline formreferred to herein as “Form M2-1” or “M2-1 Form” of Example 33. The M2-1Form of Example 33 comprises two molecules of methanol for each moleculeof Example 33.

In one embodiment, the M2-1 Form of the compound of Example 33 ischaracterized by unit cell parameters approximately equal to thefollowing:

Cell dimensions:

-   -   a=7.41 Å    -   b=9.74 Å    -   c=44.55 Å    -   α=90.0°    -   β=90.0°    -   γ=90.0°

Space group: P2₁2₁2₁

Molecules of Example 33/asymmetric unit: 1

Volume/Number of molecules in the unit cell=3214 Å³

Density (calculated)=1.346 g/cm³,

wherein the unit cell parameters of Form M2-1 are measured at atemperature of about 173 K.

In another embodiment, M2-1 form of Example 33 is characterized by asimulated powder x-ray diffraction (PXRD) pattern substantially inaccordance with the pattern shown in FIG. 11 and/or by an experimentalPXRD pattern substantially in accordance with the pattern shown in FIG.11.

In yet an even further embodiment, the M2-1 Form of Example 33 ischaracterized by fractional atomic coordinates substantially as listedin Table 7.

TABLE 7 Fractional Atomic Coordinates of Example 33, Form M2-1Calculated at a Temperature of about 173 K; Atomic Coordinates (x10⁴)Atom X Y Z Cl1 0.4450 −0.0974 0.0917 Cl2 0.2679 0.9390 −0.0104 N1 0.71460.2778 0.1831 C1 0.6840 −0.0285 0.1346 C2 0.4628 0.1463 0.1208 C3 0.75740.0528 0.1572 C4 0.5932 0.3851 0.1807 C5 0.4797 0.3617 0.1559 C6 0.43640.5908 0.1933 C7 0.5330 0.2289 0.1438 C8 0.3277 0.5712 0.1678 C9 0.57440.4989 0.1993 C10 0.3475 0.4586 0.1493 C11 0.6778 0.1810 0.1617 C120.5397 0.0174 0.1173 C13 0.4025 0.7166 0.2133 O1 0.2131 0.7465 0.2141C14 0.9038 0.0063 0.1779 C15 0.4684 0.6951 0.2453 C16 0.4889 0.84190.1994 O2 0.9372 0.0751 0.2007 N2 0.9916 −0.1089 0.1715 C17 0.31000.1985 0.1022 C18 0.1348 0.1615 0.1093 C19 0.1945 0.3479 0.0644 C200.0197 0.3118 0.0715 C21 −0.0095 0.2166 0.0941 C22 0.3427 0.2931 0.0791C23 0.5305 0.3367 0.0708 N3 0.2226 0.4569 0.0426 C24 0.2578 0.41910.0134 N4 0.2870 0.5312 −0.0066 C25 0.2192 0.5925 0.0539 C26 0.27410.6673 0.0027 C27 0.2455 0.6972 0.0321 C28 0.2898 0.7686 −0.0207 C290.3530 0.5950 −0.0567 C30 0.3340 0.4967 −0.0359 C31 0.3249 0.7337−0.0493 O3 0.1923 0.6096 0.0807 O4 0.2649 0.3023 0.0050 O5 −0.05680.6980 0.1220 C32 −0.1535 0.5826 0.1313 O6 0.9895 0.0341 0.2613 C330.9227 −0.0982 0.2682 H1 0.8003 0.2727 0.1961 H2 0.7322 −0.1151 0.1310H3 0.2399 0.6362 0.1632 H4 0.6524 0.5129 0.2154 H5 0.2733 0.4474 0.1327H6 0.1580 0.6793 0.2204 H7 0.4410 0.7750 0.2571 H8 0.5965 0.6803 0.2452H9 0.4092 0.6166 0.2538 H10 0.4409 0.8558 0.1796 H11 0.6171 0.82860.1982 H12 0.4636 0.9209 0.2116 H13 1.0747 −0.1382 0.1834 H14 0.9653−0.1543 0.1555 H15 0.1144 0.0986 0.1246 H16 −0.0771 0.3508 0.0613 H17−0.1264 0.1899 0.0990 H18 0.5554 0.3096 0.0504 H19 0.6156 0.2937 0.0840H20 0.5405 0.4346 0.0725 H21 0.2431 0.7886 0.0381 H22 0.3851 0.5712−0.0762 H23 0.3524 0.4052 −0.0410 H24 0.3306 0.8009 −0.0641 H25 0.02540.6742 0.1108 H26 −0.0765 0.5242 0.1430 H27 −0.1958 0.5332 0.1140 H28−0.2548 0.6110 0.1432 H29 0.9836 0.0467 0.2431 H30 0.8087 −0.1118 0.2584H31 0.9071 −0.1064 0.2896 H32 1.0070 −0.1664 0.2614 — — — —

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of the aspects and/or embodimentsof the invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment or embodiments to describe additional embodiments.It is also to be understood that each individual element of theembodiments is meant to be combined with any and all other elements fromany embodiment to describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of theCompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

a) Wermuth, C. G. et al., The Practice of Medicinal Chemistry, Chapter31, Academic Press (1996);

b) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985);

c) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, ATextbook of Drug Design and Development, pp. 113-191, Krogsgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991); and

d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism,Wiley-VCH (2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to Btk, or effective to treat or prevent autoimmune and/orinflammatory disease states, such as multiple sclerosis and rheumatoidarthritis.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as -CD₃.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g., magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodium croscarmellose,corn starch, and alginic acid; binding agents, such as, for example,starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricatingagents, such as, for example, magnesium stearate, stearic acid, andtalc. Additionally, a tablet can either be uncoated, or coated by knowntechniques to either mask the bad taste of an unpleasant tasting drug,or delay disintegration and absorption of the active ingredient in thegastrointestinal tract thereby sustaining the effects of the activeingredient for a longer period. Exemplary water soluble taste maskingmaterials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, anantioxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e., CAPTISOL®), cosolvent solubilization (i.e.,propylene glycol) or micellar solubilization (i.e., Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR® surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

Utility

The compounds of the invention modulate kinase activity, including themodulation of Btk. Other types of kinase activity that may be modulatedby the compounds of the instant invention include, but are not limitedto, the Tec family of compounds, such as BMX, Btk, ITK, TXK and Tec, andmutants thereof.

Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the modulation of kinase activity, andparticularly the selective inhibition of Btk activity. Such conditionsinclude B-cell mediated diseases in which cytokine levels are modulatedas a consequence of intracellular signaling.

As used herein, the terms “treating” or “treatment” encompass either orboth responsive and prophylaxis measures, e.g., measures designed toinhibit or delay the onset of the disease or disorder, achieve a full orpartial reduction of the symptoms or disease state, and/or to alleviate,ameliorate, lessen, or cure the disease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of Btk, compounds ofFormula (I) are useful in treating cytokine-associated conditionsincluding, but not limited to, inflammatory diseases such as Crohn's andulcerative colitis, asthma, graft versus host disease, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosis, psoriasis;destructive bone disorders such as bone resorption disease,osteoarthritis, osteoporosis, multiple myeloma-related bone disorder;proliferative disorders such as acute myelogenous leukemia, chronicmyelogenous leukemia; angiogenic disorders such as angiogenic disordersincluding solid tumors, ocular neovasculization, and infantilehaemangiomas; infectious diseases such as sepsis, septic shock, andShigellosis; neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease, cerebral ischemias or neurodegenerative diseasecaused by traumatic injury, oncologic and viral diseases such asmetastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIVinfection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic (3-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, Kawasaki disease, chronic inflammatorydemyelinating polyneuropathy (CIDP), dermatomyositis, uveitis,anti-factor-VIII disease, ankylosing spondylitis, myasthenia gravis,Goodpasture's disease, antiphospholipid syndrome, ANCA-associatedvasculitis, dermatomyositis/polymyositis, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption disease, allograft rejections, fever and myalgias due toinfection, cachexia secondary to infection, myeloid formation, scartissue formation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from Crohn's and ulcerative colitis, allograftrejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis,psoriatic arthritis, and pemphigus vulgaris. Alternatively preferredmethods of treatment are those wherein the condition is selected fromischemia reperfusion injury, including cerebral ischemia reperfusionsinjury arising from stroke and cardiac ischemia reperfusion injuryarising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In addition, the Btk inhibitors of the present invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2). Accordingly, additional Btk-associated conditions includeedema, analgesia, fever and pain, such as neuromuscular pain, headache,pain caused by cancer, dental pain and arthritis pain. The inventivecompounds also may be used to treat veterinary viral infections, such aslentivirus infections, including, but not limited to equine infectiousanemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “Btk-associated condition” or “Btk-associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is affected by Btk kinase activity.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit Btk.

One embodiment provides methods for treating such Btk kinase-associatedconditions, comprising administering to a subject in need thereof atleast one compound of Formula (I). A therapeutically-effective amountfor treating such conditions may be administered. The methods of thepresent embodiment may be employed to treat Btk kinase-associatedconditions such as treatment of allergic disorders and/or autoimmuneand/or inflammatory diseases including, but not limited to, SLE,rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenicpurpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis(MS), transplant rejection, Type I diabetes, membranous nephritis,inflammatory bowel disease, autoimmune hemolytic anemia, autoimmunethyroiditis, cold and warm agglutinin diseases, Evans syndrome,hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP),sarcoidosis, Sjögren's syndrome, peripheral neuropathies (e.g.,Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

The methods of treating Btk kinase-associated conditions may compriseadministering at least one compound of Formula (I) alone or incombination with each other and/or other suitable therapeutic agentsuseful in treating such conditions. Therapeutically-effective amounts ofat least one compound of Formula (I) and other suitable therapeuticagents for treating such conditions may be administered. Accordingly,“therapeutically effective amount” is also intended to include an amountof the combination of compounds claimed that is effective to treat Btkkinase-associated conditions. The combination of compounds is preferablya synergistic combination. Synergy, as described, for example, by Chouet al., Adv. Enzyme Regul., 22:27-55 (1984), occurs when the effect (inthis case, inhibition of Btk) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedanti-Btk effect, or some other beneficial effect of the combinationcompared with the individual components.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), 4-substituted imidazo[1,2-A]quinoxalines as disclosed in U.S.Pat. No. 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitricoxide, and other immunosuppressants; nuclear translocation inhibitors,such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs(NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such asprednisone or dexamethasone; antiviral agents such as abacavir;antiproliferative agents such as methotrexate, leflunomide, FK506(tacrolimus, PROGRAF®); cytotoxic drugs such as azathiprine andcyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodiesor soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) orderivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating Btkkinase-associated conditions, including IL-1, IL-6, IL-8, IFNγ andTNF-α-mediated conditions, as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Another embodiment provides the compounds of Formula (I) for use intherapy. In the present embodiment, the use in therapy may include theadministration of a therapeutically-effective amount of a compound ofFormula (I).

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for the treatment or prophylaxisof an allergic disorder and/or autoimmune and/or inflammatory disease.In the present embodiment, the use for the manufacture of a medicamentmay include the administration of a therapeutically-effective amount ofa compound of Formula (I) for the treatment of prophylaxis of anallergic disorder and/or autoimmune and/or inflammatory disease.

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for treatment of cancer. Thepresent embodiment may include the use for the manufacture of amedicament includes the administration of a therapeutically-effectiveamount of a compound of Formula (I) for the treatment of prophylaxis ofan allergic disorder and/or autoimmune and/or inflammatory disease.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,Gantrez); and agents to control release such as polyacrylic copolymer(e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents andstabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species, that are affected by mediation of Btk enzyme levels.

Examples of compounds of Formula (I) as specified in the “Examples”section below, have been tested in one or more of the assays describedbelow.

In one embodiment, the compounds of Formula (I) inhibit Btk enzymes withIC₅₀ values of 6 nM or less, for example, from 0.001 to 6 nM, asmeasured by the Human Recombinant Btk enzyme assay. Preferably, thecompounds of Formula (I) inhibit Btk enzymes with IC₅₀ values of 2 nMand less, for example, from 0.001 to 2 nM. Other preferred compoundsinhibit Btk enzymes with IC₅₀ values of 1.0 nM and less, for example,from 0.001 to 1.0 nM.

In one embodiment, the compounds of Formula (I) have reduced inhibitionof the Jak2 kinase characterized by IC₅₀ values above 50 nM, forexample, greater than 250 nM, as measured by the Jak2 tyrosine kinaseassay. Preferably, the compounds of Formula (I) inhibit Jak2 enzymeswith IC₅₀ values of greater than 400 nM, for example, with IC₅₀ valuesof greater than 700 nM.

In one embodiment, the compounds of Formula (I) have kinase selectivityratios of Btk inhibition activity over Jak2 inhibition activitycharacterized by ratios of Jak2 IC₅₀ inhibition values, as measured bythe Jak2 tyrosine kinase assay, to Btk IC₅₀ inhibition values, asmeasured by the Human Recombinant Btk enzyme assay, of 150 and greater,for example, ratios of 300 and greater. Preferably, the compounds ofFormula (I) have ratios of Jak2 IC₅₀ inhibition values to Btk IC₅₀inhibition values of 400 and greater, for example, ratios of 500 andgreater.

In one embodiment, the compounds of Formula (I) have improved potency inthe whole blood BCR-stimulated CD₆₉ expression assay with IC₅₀ values of250 nM or less, for example, from 0.1 to 250 nM. More preferably, thecompounds of Formula (I) have potency in the whole blood BCR-stimulatedCD₆₉ expression assay with IC₅₀ values of 160 nM or less, for example,from 0.1 to 160 nM; and with IC₅₀ values of 100 nM or less, for example,from 0.1 to 100 nM.

Methods of Preparation

Compounds of Formula (I) can be prepared using methods shown in Scheme1.

Substituted boronic esters 1, wherein Z represents a substitutedmonocyclic or fused bicyclic heterocyclic ring (substituent Q incompounds of Formula (I)), can be reacted with substitutedcarbazolecarboxamides or tetrahydrocarbazolecarboxamides 2 (wherein Y isan appropriate group such as Br, Cl or trifluoromethanesulfonyloxy) toprovide compounds 3. This reaction may be performed by using a suitablebase such as potassium carbonate, cesium carbonate or tripotassiumphosphate, and a suitable catalyst such astetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride, or1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride, in asuitable solvent such as dioxane or tetrahydrofuran, optionally with asuitable cosolvent such as water. Such coupling reactions are commonlyknown as Suzuki-Miyaura coupling reactions, and are well known in thechemical literature (see, for example, Heravi, M. M. et al.,Tetrahedron, 68:9145 (2012), and references cited therein).

Due to the non-symmetric nature of the rings connected by the singlebonds labeled a and b in Scheme 1, and due to limited rotation aboutthese bonds caused by steric hindrance, compounds of the currentinvention display chirality, known as atropisomerism. Thus, undercertain conditions, such as chromatography on a chiral stationary phase,the four diastereomeric atropisomers (arising from limited rotationabout the two stereogenic axes) can be observed as four separate peaksin the chromatogram. Compounds of Formula (I) can be isolated either asstable mixtures of from two to four diastereomeric atropisomers, or assingle stable atropisomers.

Since 1 is racemic, compounds 3 will normally be isolated as mixtures offour diastereomeric atropisomers. Alternatively, racemic compounds 1 canbe converted into single atropisomers 1a and 1b, with the absoluteconfigurations shown, using methods known in the art, such aspreparative chromatography on a chiral stationary phase. Suzuki-Miyauracoupling reactions as described above can then convert 1a into compounds3a, or 1b into 3b, having the absolute configurations shown about bond bbut a mixture of two configurations about bond a, as long as theconditions of the Suzuki-Miyaura coupling reaction are such thatisomerization about bond b does not occur. Compounds 3a and 3b will thusexist as a mixture of two diastereomeric atropisomers.

As shown in Scheme 2, compounds 3, which are mixtures of fourdiastereomeric atropisomers, can be separated into four single stablediastereomeric atropisomers 3c, 3d, 3e and 3f, using methods known inthe art, such as chromatography on a chiral stationary phase.Alternatively, compounds 3a (mixtures of two diastereomericatropisomers) can be separated into single stable atropisomers 3c and3d, and compounds 3b (mixtures of two diastereomeric atropisomers) canlikewise be separated into single stable atropisomers 3e and 3f

In the case where 2 is a substituted tetrahydrocarbazole carboxamide(where the dashed lines represent single bonds), 2 also contains achiral center, and thus can exist as a racemate. In this case, compounds3 prepared from these compounds 2 will exist as a mixture of eightdiastereomers, each of 3a and 3b will exist as a mixture of fourdiastereomers, and each of 3c, 3d, 3e and 3f will exist as a mixture oftwo diastereomers. Any of these mixtures can also be separated intosingle stable diastereomers using methods known in the art, such aschromatography on a chiral stationary phase. Alternatively, compounds 2can be converted into two separated enantiomers using methods known inthe art, such as chromatography on a chiral stationary phase.

In some cases where one of the coupling intermediates 1 or 2 in Scheme 1is non-racemic, chiral induction can occur during the Suzuki-Miyauracoupling reactions shown in Scheme 1. In these cases, mixtures ofdiastereomers can be obtained which are not equimolar mixtures; that is,the product 3 can be a mixture of diastereomers in which one or more ofthe diastereomers, having bond a with one absolute configuration, ispresent to a greater extent than one or more diastereomers having bond awith the opposite absolute configuration.

An alternative method for the synthesis of certain compounds of Formula(I) is shown in Scheme 3. A suitably substituted4-arylimino-1H-benzo[d][1,3]oxazin-2(4H)-one 4 can react with 2 underconditions of the Suzuki-Miyaura coupling reaction as described above,to provide compounds of Formula (I) having structure 5. During thecourse of the reaction, the 4-arylimino-1H-benzo[d][1,3]oxazin-2(4H)-onemoiety present in 4 rearranges to the 3-arylquinazoline-2,4(1H,3H)-dionemoiety present in the reaction product 5.

Compounds 1 of Scheme 1, used in the preparation of compounds of Formula(I), can be prepared by a variety of methods. Some of these methods areshown in Scheme 4. An isatoic anhydride 6 can react with a substitutedaniline 7 (wherein Y′ is an appropriate group such as Br, Cl ortrifluoromethanesulfonyloxy) to produce an amide 8. Such reactions canbe carried out under a variety of conditions, for example by heating ina suitable solvent, or by heating in the presence of an auxiliaryreagent such as trimethylaluminum. A compound 8 can be converted into asubstituted quinazolinedione 9, for example by treatment in a suitablesolvent with phosgene or triphosgene. Optionally, 9 can be converted tothe corresponding boronate ester 10 (which is an example of a compound 1of Scheme 1) using methods well known in the chemical literature (see,for example, Ishiyama, T. et al., Tetrahedron, 57:9813 (2001), andreferences cited therein). Examples of such methods are the reaction of9 with a borylating reagent such as4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) or5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) in the presence of abase such as potassium acetate and a suitable catalyst such as1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride in asuitable solvent.

Alternatively, a compound 9 can optionally be converted into a compound11 where R_(a) is an alkyl group, using methods known well known in thechemical literature, for example by treatment with an alkylating agentsuch as iodomethane or trideuteroiodomethane in the presence of asuitable base such as cesium carbonate. A compound 11 can then beconverted into the corresponding boronate ester 12 (which is an exampleof compound 1 of Scheme 1) using the same methods described above. Acompound 10 can also be optionally converted into the correspondingcompound 12 by methods similar to those described for the conversion of9 into 11.

Compounds 10 and 12 display chirality due to hindered rotation about thesingle bond connecting the substituted phenyl ring to thequinazolinedione moiety. If desired, these compounds can be resolvedinto separate enantiomeric atropisomers, for example by chromatographyon a chiral stationary phase. The separated enantiomeric atropisomers of10 can then optionally be converted into stable enantiomericatropisomers of 12 as described above to provide certain examples of thecompounds 1a or 1b of Scheme 1. Likewise, racemic quinazolinediones 12can also be resolved into separate enantiomeric atropisomers.

An alternative synthesis of intermediate compounds 8 of Scheme 4 isshown in Scheme 5. A substituted 2-nitrobenzoic acid 13 can be convertedto a compound 14 using well-known amide bond forming reactions, forexample by conversion of 8 to the corresponding carboxylic acid chlorideand reaction with a substituted aniline 7, or by direct reaction of 13and 7 in the presence of a suitable coupling reagent suchO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), or a mixture of1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) and1-hydroxybenzotriazole hydrate (HOBT), using methods well known in theliterature. The nitro group of 14 can then be reduced, using one of awide variety of methods known in the literature, to give a compound 8 ofScheme 4.

Compounds 4 of Scheme 3 can be prepared using the method shown in Scheme6. An N-substituted isatoic anhydride 15, wherein R_(a) is an alkylgroup, can react with a substituted aniline 7 to produce an amide 16.Such reactions can be carried out under a variety of conditions asdescribed above, for example by heating in a suitable solvent, or byheating in the presence of an auxiliary reagent such astrimethylaluminum. A compound 16 can be converted into a substitutedaryliminobenzoxazinone 17, for example by treatment in a suitablesolvent with phosgene or triphosgene. A compound 17 can then beconverted into the corresponding boronate ester 4 using methods similarto those described above for the conversion of a compound 10 or acompound 11 into a compound 12 (see Scheme 4).

Some additional methods which can be used to prepare certain compounds1, used in the preparation of compounds of Formula (I), are shown inScheme 7. A substituted pyridyl-2-acetic acid 18, or a salt of asubstituted pyridyl-2-acetic acid such as a sodium salt (which areeither commercially available or can be prepared by methods well knownin the chemical literature), can be reacted with an aniline 7 under avariety of methods well known in the chemical literature to provide anamide 19. For example, the reaction can be performed in the presence ofa coupling reagent such asO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), or a mixture of1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) and1-hydroxybenzotriazole hydrate (HOBT). An amide 19 can be converted intothe corresponding substituted 1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione20 by heating with a reagent such as carbonyldiimidazole in anappropriate solvent such as toluene. A compound 20 can be converted intothe corresponding boronate ester 21 (which is an example of anintermediate 1 of Scheme 1) using methods previously described (seeScheme 4). Alternatively, a compound 19 can be converted into thecorresponding boronate ester 22 using methods previously described (seeScheme 4), followed by conversion of 22 to 21 by heating with a reagentsuch as carbonyldiimidazole.

In Scheme 7, the pyridyl ring in the structures shown can also bereplaced with another nitrogen heterocycle, such as a thiazole. In thiscase, the corresponding compounds 20 and 21 will contain a5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione moiety in place of the1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione moiety shown.

Compounds 21 display chirality due to hindered rotation about the singlebond joining the substituted phenyl ring with the substituted1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione moiety. If desired, theseracemic compounds can be resolved into separate enantiomericatropisomers, for example by chromatography on a chiral stationaryphase, to provide certain examples of the intermediates 1a and 1b ofScheme 1.

Preparation of a compound 1 of Scheme 1, wherein Z represents asubstituted pyrimidine-1,3-dione moiety, can be achieved using themethod shown in Scheme 8, following a general procedure reported by Cao,J. et al. (Synthetic Commun., 39:205 (2009)). Compound 23 can beprepared by reacting p-methoxybenzylamine, methyl acrylate and phenylhypobromoselenoite. This material can be reacted with an appropriatearyl isocyanate 24 (which can be prepared from the aniline 7 shown inScheme 4, using methods well known in the chemical literature) toprovide the substituted dihydropyrimidine-1,3-dione 25. Treatment ofthis compound with an oxidizing agent such as hydrogen peroxide canprovide the substituted pyrimidine-1,3-dione 26. Removal of thep-methoxybenzyl group of 26 can be achieved using a number of methodsreported in the chemical literature, for example by treatment with amixture of trifluoromethanesulfonic acid and trifluoroacetic acid (asreported by Wu, F. et al., J. Org. Chem., 69:9307 (2004)). The resultingpyrimidine-1,3-dione 27 can be reacted with an aryl boronic acid such as4-fluorobenzeneboronic acid, for example using conditions described byJacobsen, M. F. et al. (J. Org. Chem., 71:9183 (2006)) to provide 28(wherein Ar represents 4-fluorophenyl). This can then be converted tothe boronate ester 29, which is an example of a compound 1 of Scheme 1,using methods similar to those described above.

Compounds 2 shown in Scheme 1, used in the preparation of compounds ofFormula (I), can be prepared using procedures shown in Scheme 9. Asubstituted 2-aminobenzoic acid 30 (known in the literature, or preparedusing procedures known in the literature) can be converted to thecorresponding 2-hydrazinylbenzoic acid 31 as the hydrochloric acid saltusing methods well known in the literature, for example by conversion tothe corresponding diazonium salt by treatment with sodium nitrite inaqueous hydrochloric acid, followed by reduction with tin(II) chloride.Reaction of 31 with ethyl 3-oxocyclohexanecarboxylate 32 (which can beprepared from ethyl 3-hydroxybenzoate; see for example Hirsch, J. etal., J. Org. Chem., 51:2218 (1986)) in a suitable solvent with anappropriate catalyst, for example ethanol with hydrochloric acid,toluene with p-toluenesulfonic acid or trifluoroacetic acid, or aceticacid (in which case the solvent also can serve as the catalyst), canprovide the corresponding tetrahydrocarbazole derivative 33. Thisreaction is commonly known as the Fischer indole synthesis, and is wellknown in the chemical literature (for example, see Kamata, J. et al.,Chem. Pharm. Bull., 52:1071 (2004)). Alternatively, the Fischer indolesynthesis can be carried out in two consecutive steps: 31 can react with32 under suitable conditions (such as in an appropriate solvent such asethanol or toluene, optionally with a suitable catalyst such asp-toluenesulfonic acid) to form an intermediate hydrazone, which can beisolated and then reacted further under suitable conditions (forexample, ethanol with hydrochloric acid, acetic acid with zinc chloride,or toluene with trifluoroacetic acid) to provide 33.

A carboxylic acid 33 can be converted to the corresponding carboxamide34 using methods well known in the chemical literature, for example byconversion of 33 to the acid chloride by treatment with oxalyl chlorideor thionyl chloride, followed by treatment with ammonia; or by treatmentof 33 with ammonia in the presence of a coupling reagent such ascarbodiimide, or a mixture ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. Conversion of atetrahydrocarbazole 34 to the corresponding carbazole 35 can beperformed using methods well known in the chemical literature, forexample by treatment of 34 with an oxidizing agent such as2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent.

Alternatively, the order of the amide formation and oxidation steps canbe reversed to convert 33 to 35. Thus, a compound 33 can be oxidizedusing the procedure described above, or a similar procedure, to give thecorresponding compound 36. The carboxylic acid of this compound can thenbe converted into the corresponding primary amide, again using aprocedure described above or a similar procedure, to give thecorresponding compound 35.

Conversion of 35 to the corresponding tertiary carbinol substitutedcarbazolecarboxamide 37 (which is an example of compound 2 in Scheme 1)can be performed using methods well known in the chemical literature,for example by treatment of 35 with a reagent such as methyllithium,methylmagnesium bromide or methylmagnesium chloride. Alternatively,conversion of 34 to the corresponding tertiary carbinol substitutedtetrahydrocarbazole carboxamide 38 (which is another example of compound2 in Scheme 1) can be performed using a similar procedure.

Compounds 33, 34 and 38 contain a chiral center, and thus exist as twoenantiomers. Preparation of 33, 34 and 38 as shown in Scheme 9 providesracemic products, which may be used to prepare compounds of Formula (I)as shown in Scheme 1. Alternatively, 33, 34 and 38 may be resolved intoseparated enantiomers, using well-known methods such as chromatographyon a chiral stationary phase.

Certain compounds 2 of Scheme 1, used to prepare compounds of Formula(I), may also be prepared using procedures shown in Scheme 10. Compound39, prepared from the appropriate 2-hydrazinylbenzoic acid as shown inScheme 9 (see U.S. Pat. No. 8,084,620, Intermediate 48-1) can be treatedwith an appropriate halogenating reagent to give 40, where R₁ is ahalogen atom. For example, treatment of 39 with a chlorinating reagentsuch as N-chlorosuccinimide can give 40 where R₁ is Cl, and treatment of39 with a fluorinating reagent such as1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)[SELECTFLUOR®] can give 40 where R₁ is F. Treatment of 40 withmethyllithium or a methylmagnesium halide as described for Scheme 9 canthen provide compounds 37 where R₁ is F or Cl (which are examples ofcompounds 2 in Scheme 1).

Compound 37 where R₁ is CN can be prepared by an alternative procedure,also shown in Scheme 10. Compound 41, which can be prepared fromcompound 39 (see U.S. Pat. No. 8,084,620, Example 73-2) can be treatedwith an iodinating reagent such as N-iodosuccinimide to provide 37 whereR₁ is I. This compound can be converted to 37 where R₁ is CN (an exampleof compound 2 in Scheme 1), for example by treatment with zinc cyanidein the presence of a catalyst such astetrakis(triphenylphosphine)palladium.

Another example of the preparation of a compound 2 of Scheme 1 is shownin Scheme 11. Using procedures described in Scheme 9 and similarprocedures, the ketone 42 (which can be prepared by reaction of diethylmalonate with cyclohex-2-enone, using a number of methods reported inthe literature) can be reacted with a hydrazinylbenzoic acid 31 to givea compound 43, which can then be converted to a compound 44 andsubsequently to a compound 45 using methods described above for Scheme9. Using methods known in the literature, for example heating withsodium chloride and water in a suitable solvent such as dimethylsulfoxide, a compound 45 can be converted to a compound 46. The estermoiety of a compound 46 can then be reduced to the carbinol usingprocedures known in the literature, for example by treatment withlithium borohydride, to give a compound 47, which is an example ofcompound 2 of Scheme 1.

EXAMPLES

Compounds of the current invention, and intermediates used in thepreparation of compounds of the current invention, can be prepared usingprocedures shown in the following examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these examples, are not meant to be limiting, but are meantto demonstrate how the compounds of the current invention can beprepared. Starting materials and reagents used in these examples, whennot prepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature. The invention is further defined in the following Examples.It should be understood that the Examples are given by way ofillustration only. From the above discussion and the Examples, oneskilled in the art can ascertain the essential characteristics of theinvention, and without departing from the spirit and scope thereof, canmake various changes and modifications to adapt the invention to varioususes and conditions. As a result, the invention is not limited by theillustrative examples set forth herein below, but rather defined by theclaims appended hereto.

In the examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being prepared).

Column chromatography was generally performed using the flashchromatography technique (Still, W. C. et al., J. Org. Chem., 43:2923(1978)), or with pre-packed silica gel cartridges using an Isco mediumpressure chromatography apparatus

(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. Preparative high performance liquid chromatography (HPLC) wasperformed using a reverse phase column (Waters SunFire C₁₈, WatersXBridge C₁₈, PHENOMENEX® Axia C₁₈, YMC S5 ODS or the like) of a sizeappropriate to the quantity of material being separated, generallyeluting with a gradient of increasing concentration of methanol oracetonitrile in water, also containing 0.05% or 0.1% trifluoroaceticacid or 10 mM ammonium acetate, at a rate of elution suitable to thecolumn size and separation to be achieved. Chiral super-critical fluidchromatographic separation of enantiomers or atropisomers was performedusing conditions described for the individual cases. Mass spectral datawere obtained by liquid chromatography-mass spectrometry usingelectrospray ionization.

Single crystal x-ray diffraction data were collected on a Bruker-AXSAPEX2 CCD system using Cu Kα radiation (λ=1.5418 Å). Indexing andprocessing of the measured intensity data were carried out with theAPEX2 software package/program suite (see the APEX2 User Manual, v1.27;Bruker AXS, Inc., WI 53711 USA). When indicated, crystals were cooled inthe cold stream of an Oxford Cryosystems cryostream cooler (Cosier, J.et al., J. Appl. Cryst., 19:105 (1986)) during data collection. Thestructures were solved by direct methods and refined on the basis ofobserved reflections using the crystallographic package SHELXTL (see theAPEX2 User Manual, v1.27; Bruker AXS, Inc., WI 53711 USA). The derivedatomic parameters (coordinates and temperature factors) were refinedthrough full matrix least-squares. The function minimized in therefinements was Σ_(W)(|F_(O)|−|F_(C)|)². R is defined asΣ∥F_(O)|−|F_(C)∥/Σ|F_(O)| whileR_(W)=[Σ_(W)(|F_(O)|−|F_(C)|)²/Σ_(W)|F_(O)|²]^(1/2) where w is anappropriate weighting function based on errors in the observedintensities. Difference maps were examined at all stages of refinement.Hydrogens were introduced in idealized positions with isotropictemperature factors, but no hydrogen parameters were varied. Unit cellparameters were obtained according to the procedure described in Stoutet al., X-Ray Structure Determination: A Practical Guide, MacMillan(1968).

Chemical names were determined using CHEMDRAW® Ultra, version 9.0.5(CambridgeSoft). The following abbreviations are used:

Abbreviations

CDI carbonyldiimidazoleDCM dichloromethaneDIEA diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxidedppf 1,1′-bis(diphenylphosphino)ferroceneDSC differential scanning calorimetryDTT dithiothreitolEDC 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochlorideEDTA ethylenediamine tetraacetateEtOAc ethyl acetateEtOH ethanolg gram(s)h hour(s)HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHOBT 1-hydroxybenzotriazole hydrate

HPLC High Pressure Liquid Chromatography

IPA isopropanolMeCN acetonitrileMeOH methanolmin minute(s)mmol millimole(s)

NBS N-bromosuccinimide NCS N-chlorosuccinimide NMP N-methylpyrrolidinone

t-butyl tertiary butylTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuran

Intermediate 13-(3-Bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione

Intermediate 1A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide

Method 1: A solution of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00g, 11.04 mmol) and 3-bromo-2-methylaniline (4.11 g, 22.08 mmol) indioxane (20 mL) in sealed reaction vessels was heated at 110° C. for 4days. The cooled mixture was treated with 10% aqueous K₂CO₃ and stirredat room temperature for 30 min. The mixture was extracted with DCM 3times, and the combined organic phases were washed with water, dried andconcentrated. The residue was triturated with ether to give a gray solid(2.50 g). The mother liquor was concentrated and the residue was againtriturated with ether to give a gray solid (230 mg). The two solids werecombined to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamideas a gray solid (2.73 g, 78% yield). Mass spectrum m/z 323, 325 (M+H)⁺.

Method 2. A suspension of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione(3.00 g, 16.6 mmol) in xylenes (50 mL) was treated with3-bromo-2-methylaniline (3.08 g, 16.6 mmol) and heated to reflux. After6 h the mixture was allowed to cool to room temperature overnight. Theresulting suspension was diluted with hexanes and the precipitate wascollected by filtration, rinsed with hexanes and air-dried to provide2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white solid(4.50 g, 84% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.69 (d, J=7.9 Hz,1H), 7.65 (br. s., 1H), 7.50-7.46 (m, 1H), 7.32 (d, J=8.1 Hz, 1H),7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H), 5.69 (br. s., 2H), 2.44 (s, 3H).

Intermediate 1

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl)carbonate (triphosgene) (6.28 g, 21.2 mmol) at room temperature andstirred for 15 min. The mixture was diluted with EtOAc, carefullytreated with saturated aqueous NaHCO₃ and stirred at room temperatureuntil gas evolution stopped. The separated organic phase was washedsequentially with saturated aqueous NaHCO₃, water and brine, and wasdried and concentrated. The residue was triturated with ether to provide3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as anoff-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351 (M+H)⁺.¹H NMR (400 MHz, chloroform-d) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1Hz, 1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m,2H), 7.21-7.17 (m, 1H), 2.28 (s, 3H).

Intermediate 28-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 2A:3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate 1] (4.80 g, 13.8 mmol) in DMF (25 mL) was treated withCs₂CO₃ (13.4 g, 41.2 mmol). The suspension was stirred at roomtemperature and treated dropwise (but quickly) with iodomethane (4.30mL, 68.7 mmol) and stirred rapidly at room temperature for 1 h. Themixture was diluted with EtOAc and water (200 mL). The organic phase wasseparated and washed sequentially with water and brine, then was driedand concentrated to provide3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dioneas a tan glassy foam (4.80 g, 96% yield). Mass spectrum m/z 363, 365(M+H)⁺.

Intermediate 2

A mixture of3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(4.80 g, 13.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.36 g,17.2 mmol), potassium acetate (3.89 g, 39.6 mmol) and PdCl₂(dppf) DCMadduct (0.540 g, 0.661 mmol) in dioxane (65 mL) was heated to reflux for2 h. After cooling to room temperature, the mixture was filtered throughCELITE® and the solids were rinsed with EtOAc. The filtrate was dilutedwith EtOAc, washed with water, and dried and concentrated. The residuewas subjected to column chromatography on silica gel (80 g), elutingwith EtOAc-hexanes (gradient from 20-50%), to provide8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (4.61 g, 85% yield). Massspectrum m/z 411 (M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.14-8.08 (m,1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H), 7.48 (ddd, J=14.0, 8.0, 1.5 Hz, 1H),7.34 (t, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36(s, 3H), 1.36 (s, 12H).

Intermediate 34-Bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

Intermediate 3A: Ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate

A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate[synthesized according to the procedure described in U.S. Pat. No.8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and NCS(recrystallized from toluene; 0.037 g, 0.277 mmol) in CCl₄ (10 mL) andDMF (2 mL) was stirred at room temperature for 112 h. The mixture wasfiltered, and the collected precipitate was washed with CCl₄ and driedovernight under vacuum. The residue was purified by columnchromatography on silica gel (40 g), eluting with hexanes, then withEtOAc-hexanes (30%, then 50%), to give ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate as a fluffywhite solid (0.071 g, 65% yield). Mass spectrum m/z 395, 397, (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.53 (d,J=1.1 Hz, 1H), 8.36 (br. s., 1H), 8.29 (s, 1H), 7.89 (dd, J=8.4, 1.5 Hz,1H), 7.74 (br. s., 1H), 4.38 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).

Alternative Preparation of Intermediate 3A

To a mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (90g, 249 mmol), CCl₄ (2900 mL), and NMP (600 mL) was added NCS (36.1 g,271 mmol). The reaction mixture was stirred at 45° C. for 2 h. Aftercooling to room temperature, the solid was collected by vacuumfiltration. The solid was stirred in methanol (1 L) at 60° C. for 2 hand then cooled to room temperature. The solid was collected and driedto give ethyl 5-bromo-8-carbamoyl-6-choro-9H-carbazole-2-carboxylate(69.5 g, 167 mmol, 67% yield) (95% purity).

The filtrate was concentrated under reduced pressure to remove CCl₄. Tothe NMP residue was then added water (2 L). The resulting precipitatewas collected and dried to give an additional 13.7 g of product (25%yield, 75% purity).

Intermediate 3

A solution of ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (4.14 g, 10.5mmol) in THF (200 mL) cooled in a dry ice-acetone bath was treatedportionwise over 30 min with 1.6 M methyllithium in hexanes (45.8 mL,73.2 mmol). The mixture was stirred at −78° C. for 60 min, then wastreated portionwise with saturated aqueous NH₄Cl. Water was added andthe mixture was extracted twice with EtOAc. The combined organic phaseswere washed twice with water. All aqueous phases were combined andextracted with DCM, and this organic phase was washed with water. Allorganic phases were combined, dried and concentrated. The residue wascrystallized from EtOAc to give a solid. The residue from concentrationof the mother liquor was purified by chromatography on silica gel (330g), eluting with EtOAc-hexanes (gradient from 0-100%), to giveadditional solid. The two solids were combined to give4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide asa light yellow solid (3.13 g, 78% yield). Mass spectrum m/z 363, 365,(M+H—H₂O)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.56 (d, J=8.6Hz, 1H), 8.29 (br. s., 1H), 8.17 (s, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.66(br. s., 1H), 7.42 (dd, J=8.6, 1.8 Hz, 1H), 1.52 (s, 6H).

Alternative Preparation of Intermediate 3

A suspension of ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (58.56 g, 148mmol) in THF (700 mL) under nitrogen was cooled to −15° C. in anacetone-dry ice bath. The mixture was treated dropwise with 3 Mmethylmagnesium chloride in THF (395 mL, 1.19 mol) at a rate that theinternal temperature remained between −15° C. and −10° C. After 5 h themixture was poured into 3 vessels, each containing ca. 1.5 L of crushedice and 500 mL of saturated aqueous NH₄Cl. The resulting mixtures wereextracted with EtOAc, and the combined organic phases were dried andconcentrated. The residue was combined with material from two additionalbatches, one starting from 146 mmol of ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate and the otherstarting from 142 mmol of ethyl5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate, and stirred for1 h in acetone (250 mL). The precipitate was collected by filtration,washed with hexane and dried to provide4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide asa solid (134.56 g). The filtrate was concentrated and the residue wasagain stirred for 1 h in acetone, forming a precipitate which wascollected by filtration, washed with hexane and dried to give additional4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide asa solid (7.36 g) for a total of 141.92 g (88% yield). The filtrate fromthe second filtration was combined with impure material from otherbatches and subjected to column chromatography on silica gel (2×1.5 kg),eluting with EtOAc-hexanes (gradient from 40-100%), providing additionalproduct.

Intermediate 41-Methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 4A: 2-Amino-N-(3-bromo-2-methylphenyl)benzamide

Method 1. A solution of 2-aminobenzoic acid (5.00 g, 36.5 mmol) andthionyl chloride (8.68 g, 72.9 mmol) in toluene (50 mL) was heated atreflux for 60 min. The mixture was concentrated in vacuo, and theresidue was suspended in THF (50 mL), cooled in an ice-water bath andtreated with 3-bromo-2-methylaniline (20.35 g, 109 mmol). The resultingsuspension was heated at reflux for 2 h. The cooled mixture was treatedwith 10% aqueous K₂CO₃ (50 mL), stirred vigorously for 15 min, andextracted with EtOAc. The organic phase was dried and concentrated. Theresidue was purified by column chromatography on silica gel to give2-amino-N-(3-bromo-2-methylphenyl) benzamide as a light yellow solid(4.70 g, 42% yield). Mass spectrum m/z 305, 307 (M+H)⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (br. s., 1H), 7.54 (dd,J=8.3, 1.2 Hz, 1H), 7.48 (dd, J=7.9, 0.9 Hz, 1H), 7.36-7.31 (m, 1H),7.15 (t, J=8.0 Hz, 1H), 6.81-6.73 (m, 2H), 5.59 (br. s., 2H), 2.45 (s,3H).

Method 2. A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g,30.7 mmol) and 3-bromo-2-methylaniline (5.70 g, 30.7 mmol) in xylenes(50 mL) was heated at reflux for 8 h. The solvent was removed bydistillation and the residue was purified by column chromatography onsilica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-50%), togive 2-amino-N-(3-bromo-2-methylphenyl)benzamide as an off-white solid(2.30 g, 24% yield).

Method 3. A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (10.00 g,61.3 mmol) in DMF (150 mL) was treated with 3-bromo-2-methylaniline(13.69 g, 73.6 mmol) and heated to reflux overnight. The cooled mixturewas diluted with water and extracted with EtOAc. The whole mixture wasfiltered to remove grey solids and the layers of the filtrate wereseparated. The organic phase was washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-50%), togive 2-amino-N-(3-bromo-2-methylphenyl)benzamide as tan solid (1.1 g, 6%yield). A second eluent from the column gave3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 4B]as a tan solid (3.4 g, 17% yield).

Intermediate 4B: 3-(3-Bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide (2.00 g, 6.55mmol) in THF (50 mL) was treated withbis(trichloromethyl)carbonate[triphosgene] (2.92 g, 9.83 mmol) andheated at reflux for 60 min. The cooled mixture was treated withsaturated aqueous NaHCO₃, extracted with EtOAc, and the combined organicphases were washed twice with saturated NaHCO₃, then with water, driedand concentrated. The residue was triturated with DCM to give a whitesolid which was collected by filtration. The residue from concentrationof the filtrate was triturated with DCM to give additional white solidwhich was collected by filtration. The two solids were combined to give3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid(2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H)⁺. ¹H NMR (400 MHz,MeOH-d₄) δ 8.07 (dd, J=7.92, 1.32 Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7.32(m, 4H), 2.20 (s, 3H). ¹H NMR (400 MHz, chloroform-d) δ 9.38 (br. s.,1H), 8.19 (dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m, 1H),7.35-7.17 (m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H).

Intermediate 4C:3-(3-Bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione

A suspension of 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione(23.02 g, 69.5 mmol) and Cs₂CO₃ (34.0 g, 104 mmol) in DMF (70 mL) cooledin an ice-water bath was treated portionwise with iodomethane (5.22 mL,83 mmol). The mixture was warmed to room temperature and stirred for 30min. The mixture was filtered and the filtrate was concentrated. Theresidue was partitioned between EtOAc and water. A precipitate whichformed was collected by filtration. The collected solid was washed withwater and dried overnight under vacuum to give a white solid. Theorganic phase of the filtrate was separated, washed 3 times with 10%aqueous LiCl, then was washed twice with water, dried and concentratedto give additional solid. The two solids were combined to give3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as awhite solid (15.56 g, 92% yield). Mass spectrum m/z 345, 347 (M+H)⁺.

Intermediate 4

A mixture of3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione (36.39g, 105 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (40.2 g, 158mmol), PdCl₂(dppf) DCM adduct (4.30 g, 5.27 mmol) and potassium acetate(31.0 g, 316 mmol) in dioxane (500 mL) and DMSO (50 mL) was heated atreflux for 24 h. Additional PdCl₂(dppf) DCM adduct (1.47 g) was addedand the mixture was heated at reflux for 6 h more. The cooled mixturewas filtered through CELITE® and the filtrate was concentrated. Theresidue was diluted with EtOAc, shaken with water, and both phases werefiltered through CELITE® to remove a black precipitate. The organicphase of the filtrate was separated, washed sequentially with water andbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (two 330 g columns), eluting withEtOAc-hexanes (gradient from 20-100%). The resulting solid wastriturated with EtOAc to give a solid which was collected by filtration.The filtrate was concentrated and crystallized from EtOAc to giveadditional solid. The mother liquor from this crystallization wasconcentrated and the residue was purified by column chromatography onsilica gel (330 g), eluting with EtOAc-hexanes (gradient from 20-50%),to give additional solid. The three solids were combined to give1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (21.2 g, 51% yield). Massspectrum m/z 393 (M+H)⁺. ¹H NMR (400 MHz,) δ 8.35 (d, J=7.9 Hz, 1H),7.64 (ddd, J=8.5, 7.3, 1.5 Hz, 1H), 7.59 (dd, 1.4 Hz, 1H), 7.33-7.27 (m,1H), 7.24-7.17 (m, 1H), 7.12 (d, J=8.1 Hz, 2H), 3.55 (s, 3H), 1.59 (s,3H), 1.39 (s, 12H).

Intermediate 58-Chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 5A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide

A suspension of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (4.00 g, 20.3mmol) and 3-bromo-2-methylaniline (5.65 g, 30.4 mmol) in xylene (20 mL)was heated at reflux for 2.5 h. The cooled mixture formed a yellowprecipitate. The mixture was diluted with hexanes, and the precipitatewas collected by filtration, washed with hexanes and dried to give2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide as a yellow solid(6.28 g, 91% yield). Mass spectrum m/z 339, 341 (M+H)⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.68 (d, J=8.1 Hz, 1H), 7.61 (br. s., 1H), 7.52-7.43 (m,3H), 7.15 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.8 Hz, 1H), 6.12 (br. s., 2H),2.44 (s, 3H).

Intermediate 5B:3-(3-Bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide (780mg, 2.30 mmol) in THF (20 mL) was treated with bis(trichloromethyl)carbonate (1.02 g, 3.45 mmol) and the solution stirred at roomtemperature for 21 h. The mixture was diluted with DCM and washedsequentially with saturated aqueous NaHCO₃, water and brine. The organicphase was dried and concentrated. The residue was purified by columnchromatography on silica gel (80 g), eluting with EtOAc-hexanes(gradient from 25-50%), to give3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione as awhite solid (800 mg, 95% yield). Mass spectrum m/z 365, 367 (M+H)⁺.

Intermediate 5C:3-(3-Bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione (1.45 g,3.97 mmol) in DMF (15 mL) was treated with Cs₂CO₃ (3.88 g, 11.9 mmol)and iodomethane (2.48 mL, 39.7 mmol) and stirred at room temperature for1.5 h. The mixture was diluted with water and a mixture of EtOAc andhexanes. The organic phase was washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (80 g), eluting with EtOAc-hexanes (gradient from 5-40%), togive3-(3-bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dioneas a white solid (1.3 g, 81% yield). Mass spectrum m/z 379, 391 (M+H)⁺.

Intermediate 5

A solution of3-(3-bromo-2-methylphenyl)-8-chloro-1-methylquinazoline-2,4(1H,3H)-dione(1.14 g, 3.00 mmol) in dioxane (20 mL) was treated with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.915 g,3.60 mmol), potassium acetate (0.884 g, 9.01 mmol), and PdCl₂(dppf) DCMadduct (0.123 g, 0.150 mmol). The mixture was sealed in a pressurereaction vial and heated at 110° C. for 4 h. The cooled mixture wasdiluted with EtOAc, filtered through CELITE®, and the filtrate waswashed with water, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (80 g), eluting with EtOAc-hexanes(gradient from 20-50%), to give8-chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (1.00 g, 78% yield). Mass spectrum m/z 427 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 8.23 (dd, J=7.8, 1.7 Hz, 1H), 7.93 (dd,J=7.5, 1.3 Hz, 1H), 7.76 (dd, J=7.9, 1.5 Hz, 1H), 7.37-7.31 (m, 1H),7.27-7.20 (m, 2H), 3.94 (s, 3H), 2.36 (s, 3H), 1.36 (s, 15H).

Intermediates 6 and 7

8-Chloro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(I-6), and8-Chloro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(I-7)

A sample of racemic8-chloro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate5] was separated by chiral super-critical fluid chromatography asfollows: column: Regis WHELK-O® R,R (3×25 cm, 5 μm); Mobile Phase:CO₂-MeOH (60:40) at 85 mL/min; sample preparation: 17 mg/mL in MeOH-MeCN(1:1). The first peak eluting from the column provided the S enantiomer,8-chloro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate6]. The second peak eluting from the column gave the R enantiomer,8-chloro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 7]. The mass spectrum and ¹H NMR for each enantiomericatropisomer were the same as those for Intermediate 5.

Intermediate 88-Chloro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione[Intermediate 5B] (1.00 g, 2.74 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.833 g,3.28 mmol), potassium acetate (0.805 g, 8.21 mmol) and PdCl₂(dppf) DCMadduct (0.112 g, 0.137 mmol) in dioxane (20 mL) was heated at 90° C. for8 h. The cooled mixture was filtered, concentrated, and the residue waspartitioned between DCM and water. The organic phase was dried andconcentrated, and the residue was purified by column chromatography onsilica gel (120 g), eluting with EtOAc-DCM (gradient from 0-10%), togive8-chloro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(782 mg, 58% yield). Mass spectrum m/z 413 (M+H)⁺.

Intermediate 91,8-Dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 9A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide

A mixture of thionyl chloride (3.15 g, 26.5 mmol) and2-amino-3-methylbenzoic acid (2.00 g, 13.23 mmol) in THF (50 mL) washeated at reflux for 2 h. The cooled mixture was concentrated and theresidue was combined with 3-bromo-2-methylaniline (4.92 g, 26.5 mmol) inTHF (50 mL) and heated at reflux for 5 h. The mixture was cooled to roomtemperature, treated with 10% aqueous K₂CO₃ and stirred at roomtemperature for 30 min. The resulting mixture was extracted 3 times withDCM, and the combined organic phases were washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-20%), togive 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide as a yellowsolid (1.71 g, 40% yield). Mass spectrum m/z 319, 321 (M+H)⁺. ¹H NMR(400 MHz, chloroform-d) δ 7.70 (d, J=7.9 Hz, 1H), 7.64 (br. s., 1H),7.50-7.40 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.70(t, J=7.6 Hz, 1H), 5.67 (br. s., 2H), 2.44 (s, 3H), 2.23 (s, 3H).

Intermediate 9B:3-(3-Bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide (1.71g, 5.36 mmol) and triphosgene (2.07 g, 6.96 mmol) in THF (20 mL) washeated at reflux for 1 h. The mixture was cooled on an ice-water bathand treated with saturated aqueous NaHCO₃. Stirring was continued untilgas evolution ceased. The resulting mixture was extracted 3 times withDCM. The combined organic phases were washed with water, dried andconcentrated. The residue was triturated with ether to give a whitesolid, collected by filtration. A second trituration of the concentratedfiltrate gave additional solid, collected by filtration. The filtratefrom this was concentrated and purified by column chromatography onsilica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), toprovide additional solid. The three solids were combined to provide3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione as awhite solid (1.69 g, 91% yield). Mass spectrum m/z 345, 347 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d): δ 8.07 (d, J=7.9 Hz, 1H), 7.70 (dd, J=7.9,1.3 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.27-7.17 (m, 3H), 2.41 (s, 3H),2.28 (s, 3H).

Intermediate 9C:3-(3-Bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione (470 mg,1.36 mmol) and Cs₂CO₃ (1.33 g, 4.08 mmol) in DMF (8 mL) was treated withiodomethane (0.85 mL, 13.6 mmol) and stirred at room temperature for 1.5h. The mixture was diluted with EtOAc, washed sequentially with waterand two portions of 10% aqueous LiCl. The combined aqueous phases wereextracted with EtOAc. The combined organic phases were washedsequentially with 10% aqueous LiCl and water, dried and concentrated togive impure3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione as awhite solid (510 mg), used without further purification. Mass spectrumm/z 359, 361 (M+H)⁺.

Intermediate 9

Using the same procedure described for the preparation of Intermediate2, 3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione(489 mg, 1.36 mmol) was converted to1,8-dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (410 mg, 74% yield). Mass spectrum m/z 407 (M+H)⁺.

Intermediates 10 and 118-Fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (I-10), and8-Fluoro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(I-11)

A sample of racemic8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate2] was separated by chiral super-critical fluid chromatography asfollows: column: (R,R)-WHELK-O® 1 (3×25 cm, 5 μm); Mobile Phase:CO₂-MeOH (70:30) at 200 mL/min, 100 bar, 30° C.; sample preparation:97.3 mg/mL in MeOH:DCM (1:1); injection; 4 mL. The first peak elutingfrom the column provided the (S) isomer,8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] as a white solid. Mass spectrum m/z 411 (M+H)⁺. ¹H NMR(400 MHz, chloroform-d) δ 8.14-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3 Hz,1H), 7.48 (ddd, J=14.0, 8.0, 1.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36 (s, 12H).

The second peak eluting from the column provided the (R) isomer,8-fluoro-1-methyl-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 11] as a white solid. Massspectrum m/z 411 (M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.13-8.08 (m,1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H), 7.48 (ddd, J=13.9, 8.1, 1.5 Hz, 1H),7.37-7.31 (m, 1H), 7.27-7.20 (m, 2H), 3.88 (d, J=7.9 Hz, 3H), 2.36 (s,3H), 1.36 (s, 12H).

Alternative Preparation of Intermediate 10

A solution of8-fluoro-3-(2-methyl-3-(S)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate19] (40 g, 101 mmol) in tetrahydrofuran (400 mL) was treated with cesiumcarbonate (99 g, 303 mmol) and iodomethane (12.6 mL, 202 mmol). Theresulting cloudy solution was stirred at room temperature overnight.Water (300 mL) was added and the reaction mixture was extracted withEtOAc (3×150 mL). The combined organic phases were washed sequentiallywith brine and water, and dried and concentrated. The residue waspurified by recrystallization from EtOAc to provide8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (38 g, 92% yield).

Intermediate 123-(3-Bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione

Intermediate 12A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide

A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol) and8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) intoluene (20 mL) was treated with 2 M trimethylaluminum in toluene (3.24mL, 6.47 mmol) at 0° C. The mixture was stirred at room temperature for10 minutes, then was heated at 70° C. overnight. The mixture was cooledto room temperature, treated with 1 N aqueous HCl and extracted 3 timeswith EtOAc. The combined organic phases were washed sequentially withsaturated aqueous NaHCO₃ and water, dried and concentrated. The residuewas subjected to column chromatography on silica gel (40 g), elutingwith EtOAc-hexanes (gradient from 0-100%), to provide2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide as a white solid(302 mg, 35% yield). Mass spectrum m/z 335, 337 (M+H)⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.72 (d, J=7.3 Hz, 2H), 7.46 (dd, J=8.0, 0.8 Hz, 1H),7.17-7.10 (m, 2H), 6.90 (dd, J=7.9, 0.9 Hz, 1H), 6.72-6.66 (m, 1H), 5.88(br. s., 2H), 3.92 (s, 3H), 2.43 (s, 3H).

Intermediate 12B:3-(3-Bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide (302mg, 0.901 mmol) and triphosgene (321 mg, 1.081 mmol) in THF (20 mL) wasstirred at room temperature for 2 h. The mixture was treated carefullywith saturated aqueous NaHCO₃ and stirred until gas evolution ceased.The mixture was extracted twice with DCM, and the combined organicphases were washed with water, dried and concentrated to provide3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (339mg) which was used without further purification. Mass spectrum m/z 361,363 (M+H)⁺.

Intermediate 12C:3-(3-Bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (535mg, 1.48 mmol), iodomethane (0.185 mL, 2.96 mmol) and Cs₂CO₃ (965 mg,2.96 mmol) in THF (20 mL) was stirred at room temperature overnight. Themixture was filtered and concentrated. The residue was dissolved in DCM,washed sequentially with saturated aqueous NaHCO₃ and water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (40 g silica), eluting with EtOAc-hexanes (gradient from0-100%), to give3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione(442 mg). Mass spectrum m/z 375, 377 (M+H)⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz,1H), 7.31-7.22 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.13 (m, 1H), 3.97 (s,3H), 3.89 (s, 3H), 2.23 (s, 3H).

Intermediate 12

A mixture of3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione(380 mg, 1.01 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (309 mg,1.22 mmol), potassium acetate (298 mg, 3.04 mmol) and PdCl₂(dppf) DCMadduct (41.4 mg, 0.051 mmol) in dioxane (20 mL) was heated at 90° C.overnight. The cooled mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (24 g), eluting with EtOAc-hexanes (gradient from 20-55%), togive8-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dionein 75% purity, used without further purification (486 mg, 85% yield).Mass spectrum m/z 423 (M+H)⁺.

Intermediate 133-(3-Bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

Intermediate 13A: 2-Amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide

A mixture of 3-bromo-2-methylaniline (1.50 g, 8.06 mmol) and6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.46 g, 8.06 mmol) intoluene (40 mL) was cooled on an ice-water bath and treated portionwisewith 2 M trimethylaluminum in toluene (10.1 mL, 20.2 mmol). The mixturewas stirred at room temperature for 30 min, then was heated at 70° C.overnight. The mixture was cooled to 0° C., carefully treated with 1 Maqueous HCl, and extracted 3 times with EtOAc. The combined organicphases were washed sequentially with saturated aqueous NaHCO₃ and water,dried and concentrated. The residue was subjected to columnchromatography on silica gel (120 g), eluting with EtOAc-hexanes(gradient from 5-40%), to provide2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 87%purity, 30% yield). Mass spectrum m/z 323, 325 (M+H)⁺. ¹H NMR (400 MHz,MeOH-d₄) δ 7.54 (1H, dd, J=8.03, 0.99 Hz), 7.48 (1H, dd, J=9.68, 3.08Hz), 7.33 (1H, d, J=7.26 Hz), 7.16 (1H, t, J=7.92 Hz), 7.04-7.12 (1H,m), 6.83 (1H, dd, J=9.02, 4.62 Hz), 2.39 (3H, s).

Intermediate 13B:3-(3-Bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide(0.893 g, 2.76 mmol) and triphosgene (0.984 g, 3.32 mmol) in THF (30 mL)was stirred at room temperature for 2 h. The mixture was carefullytreated with saturated aqueous NaHCO₃ and stirred until gas evolutionceased. The mixture was extracted twice with DCM. The combined organicphases were washed with water, dried and concentrated. The residue wastriturated with DCM to give a white solid, isolated by filtration. Thefiltrate was concentrated and subjected to column chromatography onsilica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-80%), toprovide additional solid. The two solids were combined to provide3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione as awhite solid (845 mg, 87% yield). Mass spectrum m/z 349, 351 (M+H)⁺.

Intermediate 13C:3-(3-Bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione (742 mg,2.13 mmol), iodomethane (0.159 mL, 2.55 mmol) and Cs₂CO₃ (1.039 g, 3.19mmol) in THF (20 mL) was stirred at room temperature overnight. Themixture was filtered and concentrated. The residue was dissolved in DCMand washed sequentially with saturated aqueous NaHCO₃ and water, driedand concentrated to provide3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(742 mg, 96% yield). Mass spectrum m/z 363, 365 (M+H)⁺.

Intermediate 13

A mixture of3-(3-bromo-2-methylphenyl)-6-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(742 mg, 2.04 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (623 mg,2.45 mmol), potassium acetate (602 mg, 6.13 mmol) and PdCl₂(dppf) DCMadduct (83 mg, 0.102 mmol) in dioxane (20 mL) was heated at 90° C.overnight. The cooled mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-40%), togive6-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(866 mg), used without further purification. Mass spectrum m/z 411(M+H)⁺.

Intermediate 147-Methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 14A: 2-Amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide

A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol)7-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) intoluene (20 mL) was treated with 2 M trimethylaluminum in toluene (3.24mL, 6.48 mmol) at 0° C. The mixture was stirred at room temperature for10 min, then heated at 70° C. overnight. The cooled mixture was treatedwith 1 M aqueous HCl, extracted 3 times with EtOAc, and the combinedorganic phases were washed sequentially with saturated aqueous NaHCO₃and water, dried and concentrated. The residue was purified by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 0-100%), to give a 4:1 mixture of2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide and3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione (592mg). Mass spectrum m/z 335, 337 (M+H)⁺.

Intermediate 14B:3-(3-Bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide (596mg, 1.78 mmol) and triphosgene (633 mg, 2.13 mmol) in THF (30 mL) wasstirred at room temperature for 2 h. The mixture was treated withsaturated aqueous NaHCO₃ and stirred until gas evolution ceased. Theresulting mixture was extracted twice with DCM, and the combined organicphases were washed with water, dried and concentrated. The residue waspurified by column chromatography on silica gel (40 g), eluting withEtOAc-hexanes (gradient from 0-100%), to give3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione as awhite solid (440 mg, 68% yield). Mass spectrum m/z 361, 363 (M+H)⁺.

Intermediate 14C:3-(3-Bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione (440mg, 1.22 mmol) in THF (30 mL) was treated with iodomethane (303 mg, 2.13mmol) and Cs₂CO₃ (869 mg, 2.67 mmol) at room temperature. The mixturewas stirred at room temperature overnight, then was filtered andconcentrated. The residue was dissolved in DCM and washed sequentiallywith saturated aqueous NaHCO₃ and water, dried and concentrated to give3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione(502 mg), used without further purification. Mass spectrum m/z 375, 377(M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.21 (d, J=8.8 Hz, 1H), 7.67(dd, J=7.9, 1.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.17-7.13 (m, 1H), 6.88 (dd,J=8.8, 2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 3H),2.24 (s, 3H).

Intermediate 14

A mixture of3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione(390 mg, 1.04 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (317 mg,1.25 mmol), potassium acetate (306 mg, 3.12 mmol) and PdCl₂(dppf) DCMadduct (42.4 mg, 0.052 mmol) in dioxane (20 mL) was heated at 90° C.overnight. The cooled mixture was filtered and concentrated. The residuewas purified by column chromatography on silica gel (40 g), eluting withEtOAc-hexanes (gradient from 10-55%), to give7-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(504 mg, 76% purity, 87% yield), used without further purification. Massspectrum m/z 423 (M+H)⁺.

Intermediate 157-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 15A: 2-Amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide

A mixture of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 27.6mmol) and 3-bromo-2-methylaniline (5.14 g, 27.6 mmol) in xylene (50 mL)was heated at reflux for 8 h. The cooled mixture was filtered. Thecollected solid was washed with 3 times with DCM and the combinedfiltrates were concentrated. The residue was purified by columnchromatography on silica gel (330 g), eluting with EtOAc-hexanes(gradient from 0-45%), to give2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 41%yield). Mass spectrum m/z 323, 325 (M+H)⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.65 (1H, d, J=8.14 Hz), 7.45-7.57 (3H, m), 7.14 (1H, t,J=8.03 Hz), 6.39-6.50 (2H, m), 5.80 (2H, br. s.), 2.43 (3H, s).

Intermediate 15B:3-(3-Bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65g, 11.3 mmol) in THF (50 mL) was treated with triphosgene (3.69 g, 12.4mmol) at room temperature. The solution was stirred at room temperaturefor 2 h, then was treated slowly with saturated aqueous NaHCO₃ andstirred until no more gas evolution was observed. The resulting mixturewas extracted twice with EtOAc. The combined organic phases were washedtwice with water, then with brine, dried and concentrated to give3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (4.20g), used without further purification. Mass spectrum m/z 349, 351(M+H)⁺.

Intermediate 15C:3-(3-Bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (2.70 g,7.73 mmol), iodomethane (0.580 mL, 9.28 mmol) and Cs₂CO₃ (3.78 g, 11.6mmol) in THF (20 mL) was stirred at room temperature for 3 h. Themixture was filtered and the filtrate was diluted with DCM and washedwith water. The aqueous phase was extracted with DCM, and the combinedorganic phases were dried and concentrated to give3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(2.85 g), used without further purification. Mass spectrum m/z 363, 365(M+H)⁺, 385, 387 (M+Na)⁺.

Intermediate 15

A mixture of3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(2.81 g, 7.74 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.36 g,9.28 mmol), potassium acetate (1.52 g, 15.5 mmol) and PdCl₂(dppf) DCMadduct (0.190 g, 0.232 mmol) in dioxane (20 mL) was heated at 90° C. for8 h. Additional PdCl₂(dppf) DCM adduct (0.190 g, 0.232 mmol) andpotassium acetate (0.80 g) were added and the mixture was heated at 90°C. for another 7 h. The cooled mixture was diluted with EtOAc and washedsequentially with saturated aqueous NaHCO₃ and water. The combinedaqueous phases were extracted with EtOAc. The combined organic phaseswere filtered through CELITE® and concentrated. The residue was purifiedby column chromatography on silica gel (220 g), eluting withEtOAc-hexanes (gradient from 0-40%), to give7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(1.76 g, 56% yield). Mass spectrum m/z 411 (M+H)⁺.

Intermediate 166,8-Difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 16A:N-(3-Bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide

A solution of 3,5-difluoro-2-nitrobenzoic acid (522 mg, 2.57 mmol) inDCM (10 mL) was treated with oxalyl chloride (0.337 mL, 3.86 mmol), thenwith DMF (3 drops). The resulting solution was stirred at roomtemperature for 60 min. The mixture was concentrated and the residue wasre-concentrated twice from dry DCM. The residue was dissolved in DCM (10mL) and treated dropwise with 3-bromo-2-methylaniline (478 mg, 2.57mmol), followed by dropwise addition of TEA (0.537 mL, 3.86 mmol). Theresulting mixture was stirred at room temperature overnight. The mixturewas treated with saturated aqueous NaHCO₃, forming a white precipitate.The organic phase was separated, and the aqueous phase and the whitesolid were extracted twice with DCM, then filtered. The collected solidwas washed with water and dried. The combined organic phases were driedand concentrated, and the residue was triturated with DCM to giveadditional solid. Both solids were combined with DCM and MeOH andconcentrated to giveN-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide (821 mg, 86%yield). Mass spectrum m/z 371, 373 (M+H)⁺ 393, 395 (M+Na)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.65 (s, 1H), 7.98-7.90 (m, 1H), 7.81 (d, J=8.1 Hz,1H), 7.55 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.21 (t, J=7.9 Hz,1H), 2.32 (s, 3H).

Intermediate 16B:2-Amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide

A mixture of N-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide(821 mg, 2.21 mmol), NH₄Cl (1.18 g, 22.1 mmol) and zinc (1.45 g, 22.1mmol) in MeOH (10 mL) was stirred at room temperature for 60 min. Themixture was filtered and the filtrate was concentrated. The residue wassuspended in DCM and washed with saturated aqueous NaHCO₃. The organicphase, with an insoluble precipitate, was separated from the aqueousphase and concentrated to give2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide (760 mg), usedwithout further purification. Mass spectrum m/z 341, 343 (M+H)⁺, 363,365 (M+Na)⁺.

Intermediate 16C:3-(3-Bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione

A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide(760 mg, 2.23 mmol) in THF (10 mL) was treated portionwise withtriphosgene (722 mg, 2.43 mmol). The solution was stirred at roomtemperature for 60 min, then was treated dropwise with saturated aqueousNaHCO₃ and stirred until no more gas evolution was observed. The organicphase was separated, washed with water, dried and concentrated. Theresidue was purified by column chromatography on silica gel (40 g),eluting with EtOAc-hexanes (gradient from 0-100%), to give3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione (820mg), used without further purification. Mass spectrum m/z 367, 369(M+H)⁺, 389, 391 (M+Na)⁺.

Intermediate 16

A mixture of3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione(1.43 g, 3.89 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.29 g,5.06 mmol), potassium acetate (0.956 g, 9.74 mmol) and PdCl₂(dppf) DCMadduct (0.159 g, 0.195 mmol) in dioxane (20 mL) was heated at 100° C.for 5 h. The cooled mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (40 g+12 g stacked columns), eluting with EtOAc-hexanes(gradient from 0-100%), to give6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(1.20 g, 74% yield). Mass spectrum m/z 415 (M+H)⁺.

Intermediate 178-Fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

A stirred mixture of3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate1] (0.349 g, 1.00 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.305 g,1.20 mmol), PdCl₂(dppf) DCM adduct (0.041 g, 0.050 mmol) and potassiumacetate (0.245 g, 2.50 mmol) in dioxane (20 mL) and DMSO (4 mL) wasbubbled with nitrogen for 5 min, then heated at 90° C. overnight. Thecooled mixture was partitioned between EtOAc and water. The organicphase was washed sequentially with saturated aqueous NaHCO₃, water andbrine, and dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (20:80) to give8-fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas a white solid (0.326 g, 82% yield). Mass spectrum m/z 397 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.72(dd, J=7.4, 1.5 Hz, 1H), 7.71-7.56 (m, 1H), 7.45-7.35 (m, 1H), 7.35-7.29(m, 1H), 7.29-7.16 (m, 1H), 2.22 (s, 3H), 1.33 (s, 12H).

Intermediates 18 and 198-Fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (18), and8-Fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(19)

A sample of8-fluoro-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate17] was separated by super-critical fluid chromatography as follows:column: CHIRALCEL® OD-H (5×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (70:30)at 300 mL/min, 100 bar, 40° C.; sample preparation: 103 mg/mL inDCM-MeOH (44:56); injection: 5.0 mL. The first peak eluting from thecolumn provided the R enantiomer,8-fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate18] as a white solid. The second peak eluting from the column providedthe S enantiomer,8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate19] as a white solid. The mass spectrum and ¹H NMR for each enantiomericatropisomer were the same as those for Intermediate 17.

Intermediate 208-Fluoro-1-methyl(d₃)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Intermediate 20A:3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methyl(d₃)quinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate 1] (3.00 g, 8.59 mmol) and Cs₂CO₃ (5.60 g, 17.2 mmol) inDMF (45 mL) was treated with iodomethane-d₃ (0.80 mL, 12.9 mmol) and themixture was stirred at room temperature for 1.75 h. The mixture waspoured into rapidly-stirred water (400 mL) and stirred at roomtemperature, forming a suspended solid. The precipitate was collected byfiltration, washed with water and dried under vacuum to provide3-(3-bromo-2-methylphenyl)-8-fluoro-1-methyl(d₃)quinazoline-2,4(1H,3H)-dione as an off-white solid (3.05 g, 97% yield).Mass spectrum m/z 366, 368 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (dt,J=7.9, 0.7 Hz, 1H), 7.82-7.63 (m, 2H), 7.45-7.18 (m, 3H), 2.12 (s, 3H).

Intermediate 20

A mixture of3-(3-bromo-2-methylphenyl)-8-fluoro-1-methyl(d₃)quinazoline-2,4(1H,3H)-dione(3.00 g, 8.19 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.70 g,10.7 mmol) and potassium acetate (2.41 g, 24.6 mmol) in dioxane (40 mL)was bubbled with argon with sonication for ca. 2 min, then was treatedwith PdCl₂(dppf) DCM adduct (0.335 g, 0.410 mmol). The mixture washeated at 90° C. for 15.75 h. The cooled mixture was diluted with EtOAc,filtered through CELITE®, and the solids were rinsed with EtOAc. Thecombined filtrates were concentrated, and the residue was purified bycolumn chromatography on silica gel (330 g), eluting with EtOAc-hexanes(gradient from 0-40%), to give8-fluoro-1-methyl(d₃)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dioneas an off-white solid (3.23 g, 95% yield). Mass spectrum m/z 414 (M+H)⁺.¹H NMR (400 MHz, chloroform-d) δ 8.14-8.07 (m, 1H), 7.93 (dd, J=7.4, 1.4Hz, 1H), 7.48 (ddd, J=13.9, 8.1, 1.5 Hz, 1H), 7.37-7.31 (m, 1H),7.27-7.19 (m, 2H), 2.36 (s, 3H), 1.36 (s, 12H).

Intermediates 21 and 228-Fluoro-1-methyl(d₃)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione (21), and8-Fluoro-1-methyl(d₃)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione(22)

A sample of8-fluoro-1-methyl(d₃)-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate20] was separated by super-critical fluid chromatography as follows:column: WHELK-O® R,R (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (70:30) at200 mL/min, 100 bar, 30° C.; sample preparation: 97.3 mg/mL in MeOH:DCM(1:1); injection: 4 mL. The first peak eluting from the column providedthe S enantiomer,8-fluoro-1-methyl(d₃)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 21] as a white solid. The second peak eluting from thecolumn provided the R enantiomer,8-fluoro-1-methyl(d₃)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate22] as a white solid. The mass spectrum and ¹H NMR for each enantiomericatropisomer were the same as those for Intermediate 20.

Alternative Synthesis of8-Fluoro-1-methyl(d₃)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate21]:

A solution of8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate19] (5.42 g, 13.7 mmol) in THF (100 mL) was stirred on an ice-water bathand treated with Cs₂CO₃ (6.24 g, 19.2 mmol), then with iodomethane-d₃(1.02 mL, 16.4 mmol) and the mixture was stirred at room temperature for16.25 h. The mixture was filtered, the solid was rinsed with EtOAc, andthe combined filtrates were concentrated. The residue was dissolved inEtOAc and washed sequentially with water and brine, dried andconcentrated to provide8-fluoro-1-methyl(d₃)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (5.538 g, 98% yield). Massspectrum m/z 414 (M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.11 (dq,J=7.8, 0.8 Hz, 1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H), 7.48 (ddd, J=13.9,8.1, 1.5 Hz, 1H), 7.38-7.30 (m, 1H), 7.27-7.20 (m, 2H), 2.36 (s, 3H),1.36 (s, 12H).

Intermediate 233-4-Bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

Intermediate 23A:4-Bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide

A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[synthesized according to the procedure described in U.S. Pat. No.8,084,620, Example 73-2] (2.00 g, 5.76 mmol), N-iodosuccinimide (1.69 g,7.49 mmol), and pyridine (1.9 mL, 23.0 mmol) in DMF (20 mL) was heatedat 65° C. for 2 days. The cooled mixture was diluted with EtOAc, washedtwice with 10% aqueous LiCl and then with brine. The aqueous layers wereextracted with EtOAc. The combined organic layers were dried andconcentrated, and the residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes (gradient from 50%-65%), toprovide4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide as ayellow solid (0.609 g, 23% yield). Mass spectrum m/z 473, 475(M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.49 (d, J=8.6Hz, 1H), 8.38 (s, 1H), 8.26 (br. s., 1H), 7.94 (d, J=1.1 Hz, 1H), 7.58(br. s., 1H), 7.40 (dd, J=8.6, 1.4 Hz, 1H), 5.09 (s, 1H), and 1.51 (s,6H).

Intermediate 23

A mixture of4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide(0.609 g, 1.29 mmol) and zinc cyanide (0.076 g, 0.644 mmol) in DMF (7mL) was subjected to three evacuate-fill cycles with nitrogen. Themixture was treated with tetrakis(triphenylphosphine)palladium (0.074 g,0.064 mmol) and heated overnight at 95° C. The cooled mixture wasdiluted with EtOAc, washed twice with 10% aqueous LiCl, then with brine.The aqueous layers were extracted with EtOAc. The combined organiclayers were dried and concentrated. The residue was triturated andsonicated with DCM and the precipitate was collected by filtration togive 4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a pale yellow solid (0.400 g, 83% yield). Mass spectrum m/z 372, 374(M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.55 (d, J=8.6Hz, 1H), 8.38 (s, 1H), 8.31 (br. s., 1H), 8.03 (s, 1H), 7.74 (br. s.,1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), and 1.52 (s, 6H).

Intermediate 245-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(racemic)

Intermediate 24A: 4-Bromo-2,5-difluorobenzoic acid

A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in drydiethyl ether (10 mL) cooled in a dry ice-acetone bath was treateddropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). Thesolution was stirred at −78° C. for 30 min, then was treated with apiece of dry ice. The cooling bath was removed after 5 min and themixture was stirred for another 30 min while warming to roomtemperature. The mixture was diluted with EtOAc and water. The organicphase was separated and washed twice with saturated aqueous NaHCO₃. Thecombined aqueous phases were acidified with 1 M aqueous HCl, extractedtwice with DCM, and the combined organic phases were dried andconcentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid(297 mg, 53% yield).

Intermediate 24B: 4-Bromo-5-fluoro-2-hydrazinylbenzoic acidhydrochloride

A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6 mmol) andhydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone (2 mL) washeated at 95° C. for 4 h. The cooled mixture was poured into vigorouslystirred 6 M aqueous HCl (400 mL) which was cooled in an NaCl-ice bath.The resulting precipitate was collected by filtration, washed with 6 Maqueous HCl (200 mL) and dried under vacuum to give4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a yellowsolid (1.88 g, 71% purity, 44% yield), used without furtherpurification.

Alternative Synthesis of 4-Bromo-5-fluoro-2-hydrazinylbenzoic acidhydrochloride

A suspension of 2-amino-4-bromo-5-fluorobenzoic acid (10.0 g, 42.7 mmol)in a mixture of 37% aqueous HCl (42.7 mL) and water (14.3 mL), cooledwith a NaCl-ice bath, was treated dropwise with a solution of sodiumnitrite (3.24 g, 47.0 mmol) in water (15.7 mL). When addition wascomplete, the mixture was stirred for 30 min more. A solution of tin(II)chloride dihydrate (28.9 g, 128 mmol) in 37% aqueous HCl (27.5 mL) wasadded dropwise. The cooling bath was removed and the mixture was stirredat room temperature for 45 min. The thick suspension was filtered andthe collected precipitate was washed thoroughly with water and driedovernight under reduced pressure. The solid was triturated with MeOHwith sonication, and the precipitate was collected by filtration, washedwith MeOH and dried. The filtrate was concentrated, and the residue wastriturated with DCM. The resulting solid was collected by filtration,dried and combined with the other solid to give4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 44%yield) as a white solid. Mass spectrum m/z 249, 251 (M+H)⁺.

Intermediate 24C:5-Bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid

A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride(5.37 g, 18.8 mmol), ethyl 3-oxocyclohexanecarboxylate (3.52 g, 20.7mmol) and acetic acid (3.23 mL, 56.4 mmol) in toluene (90 mL) was heatedat 110° C. for 20 h. The solvent was removed under reduced pressure, andthe residue was diluted with toluene (43 mL) and trifluoroacetic acid(11 mL). The mixture was stirred at 90-94° C. overnight. The cooledmixture was diluted with EtOAc, sonicated, and the precipitate wascollected by filtration. The filtrate was concentrated and resuspendedin EtOAc with sonication, resulting in another precipitate which wasalso collected by filtration and washed with EtOAc. The combined solidswere triturated twice with MeOH to give a solid. The combined filtrateswere concentrated and the residue was triturated with MeOH to giveadditional solid. The solids were combined to give5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid as a pale yellow solid (3.38 g). Mass spectrum m/z 384, 386 (M+H)⁺.

Intermediate 24D: Ethyl5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate

A mixture of5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid (0.513 g, 1.34 mmol), EDC (0.384 g, 2.00 mmol), and HOBT (0.307 g,2.00 mmol) in THF (10 mL) and DCM (1.65 mL) was stirred at roomtemperature for 20 min. Ammonium hydroxide (0.078 mL, 2.00 mmol) wasadded, and the mixture was stirred at room temperature for 60 min. Themixture was diluted with EtOAc and washed twice with saturated aqueousof NaHCO₃, then with brine. The aqueous layers were extracted withEtOAc, and the combined organic layers were dried and concentrated. Theresidue was triturated in MeOH with sonication to provide ethyl5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylateas a yellow solid (0.432 g, 84% yield). Mass spectrum m/z 383, 385(M+H)⁺.

Intermediate 24

A solution of ethyl5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate(10.0 g, 26.1 mmol) in THF (200 mL) at −78° C. was treated dropwise over30 min with 1.6 M methyllithium in ether (49 mL, 78 mmol). The mixturewas stirred at −78° C. for 45 min, then was treated with additionalmethyllithium solution (33 mL) over 25 min. The mixture was stirred at−78° C. for an additional 90 min, then was treated with saturatedaqueous NH₄Cl and warmed to room temperature. The mixture was dilutedwith EtOAc and washed sequentially with water and brine. The aqueouslayers were extracted with EtOAc. The combined organic layers were driedand concentrated. The residue was dissolved in EtOAc (about 100 mL) andfiltered through a pad of CELITE® topped with a pad of silica gel,washing further with EtOAc (about 1000 mL). Concentration of thefiltrate gave racemic5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamideas a pale yellow solid (9.24 g, 96% yield). Mass spectrum m/z 369, 371(M+H)⁺.

Alternative Synthesis of Intermediate 24

To a solution of ethyl5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate(10.0 g, 26.1 mmol) in tetrahydrofuran (200 mL) at −78° C. was addedmethyllithium (1.6 M in ether) (3 equiv.; 49 mL, 78 mmol) dropwise over30 min. The reaction mixture was stirred at −78° C. for 45 minutes. Anadditional 2 equivalents of methyllithium (33 mL) was added over 25min., and the reaction mixture was stirred at −78° C. for an additional1.5 h. The reaction was quenched at −78° C. with a saturated aqueoussolution of ammonium chloride and warmed to room temperature. Themixture was diluted with ethyl acetate, washed with water, and washedwith brine. The organic layer was collected, and the aqueous layers weresequentially extracted with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was dissolved in ˜100 mL of ethyl acetate andfiltered through a pad of CELITE® topped with a pad of silica gel in a600 mL fritted funnel using ethyl acetate (˜1 L). Concentration underreduced pressure afforded5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboximide(9.24 g, 25.03 mmol, 96% yield) as a pale yellow solid.

Intermediates 25 and 26(R)-5-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(I-25), and(S)-5-Bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(I-26)

A sample of racemic5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate24] was separated by chiral super-critical fluid chromatography asfollows: column: CHIRALPAK® OD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH(70:30) at 150 mL/min, 40° C. The first peak eluting from the columnprovided(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate25]. The second peak eluting from the column provided(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate26]. The mass spectra and NMR spectra of the two enantiomers were thesame. Mass spectrum m/z 369, 371 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ10.96 (s, 1H), 8.07 (br. s., 1H), 7.55 (d, J=10.3 Hz, 1H), 7.50 (br. s.,1H), 4.24 (s, 1H), 3.26 (dd, J=15.8, 4.4 Hz, 1H), 2.93 (dd, J=17.1, 4.6Hz, 1H), 2.72 (t, J=11.7 Hz, 1H), 2.48-2.40 (m, 1H), 2.12 (d, J=9.2 Hz,1H), 1.70-1.62 (m, 1H), and 1.32 (qd, J=12.4, 5.3 Hz, 1H).

Alternative SFC Separation to Give Intermediate 26

CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (55:45) at 150mL/min, 40° C. The first peak eluting from the column provided(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate 26]. The second peak eluting from the column provided(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate 25].

Intermediate 274-Bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

Intermediate 27A:4-Bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic acid

A solution of5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid (2.87 g, 7.47 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (3.73g, 16.4 mmol) in THF (45 mL) was heated at 60° C. for 90 min. The cooledmixture was diluted with EtOAc (about 50 mL) and stirred for 60 min. Theresulting precipitate was collected by filtration, washed with EtOAc anddried. The filtrate was concentrated, and the residue was trituratedwith MeOH with sonication, filtered, and the precipitate was washed withMeOH and dried. The two precipitates were combined to give4-bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic acid as apale yellow solid (2.39 g, 84% yield). Mass spectrum m/z 380, 382(M+H)⁺.

Intermediate 26B: Ethyl5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate

A mixture of4-bromo-7-(ethoxycarbonyl)-3-fluoro-9H-carbazole-1-carboxylic acid (2.39g, 6.29 mmol), EDC (1.81 g, 9.43 mmol) and HOBT (1.44 g, 9.43 mmol) inTHF (30 mL) and DCM (5 mL) was stirred at room temperature for 20 min.Ammonium hydroxide (0.367 mL, 9.43 mmol) was added, and the mixture wasstirred at room temperature for 4 h. The mixture was diluted with EtOAc,washed twice with saturated aqueous NaHCO₃, then with brine. The aqueouslayers were extracted with EtOAc, and the combined organic layers weredried and concentrated. The residue was triturated with MeOH withsonication to provide ethyl5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate as a pale yellowsolid (2.26 g, 95% yield). Mass spectrum m/z 379, 381 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.70 (d, J=8.3 Hz, 1H), 8.51 (d,J=1.1 Hz, 1H), 8.29 (br. s., 1H), 8.10 (d, J=10.3 Hz, 1H), 7.87 (dd,J=8.5, 1.5 Hz, 1H), 7.74 (br. s., 1H), 4.37 (q, J=6.9 Hz, 2H), and 1.37(t, J=7.1 Hz, 3H). ¹H NMR (500 MHz, MeOH-d₄) δ 8.77 (d, J=8.2 Hz, 1H),8.36 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H),4.12 (q, J=7.0 Hz, 2H), 1.58-1.36 (m, 4H), and 1.26 (t, J=7.2 Hz, 3H).

Alternative Synthesis of Ethyl5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate

A mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate[synthesized according to the procedure described in U.S. Pat. No.8,084,620, Intermediate 48-1] (0.100 g, 0.277 mmol) and1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) [SELECTFLUOR®] (0.100 g, 0.554 mmol) in THF (2mL) and MeCN (2 mL) was heated at 60° C. overnight. The cooled mixturewas filtered and the filtrate was concentrated. The residue was purifiedusing reverse-phase preparative HPLC to give ethyl5-bromo-8-carbamoyl-3-fluoro-9H-carbazole-2-carboxylate as a tan solid(0.035 g).

Intermediate 27

A solution of ethyl5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (0.500 g, 1.32mmol) in THF (9.0 mL) at −78° C. was treated dropwise over 10 min with1.6 M methyllithium in ether (2.47 mL, 3.96 mmol). The mixture wasstirred at −78° C. for 30 min, then was treated with additionalmethyllithium solution (1.65 mL, 2.64 mmol) and the mixture was stirredat −78° C. for 45 min more. The mixture was treated with saturatedaqueous NH₄Cl and allowed to warm to room temperature. The mixture wasdiluted with EtOAc and washed sequentially with water and brine. Theaqueous layers were extracted with EtOAc and the combined organic layerswere dried and concentrated to provide a pale yellow solid which waspurified by reverse phase preparative HPLC. The appropriate fractionswere neutralized with saturated aqueous NaHCO₃ and concentrated. Theresidue was partitioned between EtOAc and water, and the organic layerwas washed with brine. The aqueous layers were extracted with EtOAc, andthe combined organic layers were dried and concentrated to provide4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide asa pale yellow solid (0.240 g, 50% yield). Mass spectrum m/z 347, 349(M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.50 (d, J=8.6Hz, 1H), 8.22 (br. s., 1H), 7.96 (d, J=10.3 Hz, 1H), 7.94 (d, J=1.1 Hz,1H), 7.65 (br. s., 1H), 7.39 (dd, J=8.5, 1.5 Hz, 1H), 5.09 (s, 1H), and1.51 (s, 6H).

Alternative Synthesis of4-Bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

A solution of ethyl5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (10 g, 26.4mmol) in THF (300 mL) was cooled in an ice-water bath and treateddropwise with 3.0 M methylmagnesium chloride in THF (70.3 mL, 211 mmol).The solution was stirred at 0° C. for 18 h. The mixture was poured into1000 mL of well-stirred saturated aqueous NH₄Cl cooled in an ice-waterbath. The resulting mixture was diluted with water and extracted twicewith EtOAc. The combined organic phases were washed twice with water,then with brine, and dried and concentrated. The residue was purified bycolumn chromatography on silica gel (330 g), eluting with EtOAc-DCM(gradient from 20-100%), to give4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(6.36 g, 65% yield).

Intermediate 284-Bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide

Intermediate 28A: 5-Bromo-2-iodo-4-methylaniline

A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol),N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodoniumtetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred atroom temperature overnight. The mixture was diluted with DCM, washedsequentially with saturated aqueous NaHSO₃ and water, and dried andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), toprovide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63%yield). Mass spectrum m/z 312, 314 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s,3H).

Intermediate 28B: 2-Amino-4-bromo-5-methylbenzonitrile

A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinccyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to threeevacuate-fill cycles with nitrogen. The mixture was treated withtetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heatedat 90° C. overnight. The cooled mixture was diluted with EtOAc andwashed sequentially with 10% aqueous LiCl (twice) and brine. The aqueouslayers were extracted with EtOAc, and the combined organic layers weredried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially1%, 2.5%, 5% and 50%), to give a brown solid. The residue was furtherpurified by trituration with MeOH to give three crops of solid. Thefiltrate was again purified by column chromatography on silica gel,eluting with EtOAc-hexanes (5%, then 10%). The resulting solid wascombined with the other crops to provide2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield).Mass spectrum m/z 211, 213 (M+H)⁺.

Intermediate 28C: 2-Amino-4-bromo-5-methylbenzoic acid

A mixture of 2-amino-4-bromo-5-methylbenzonitrile (2.95 g, 14.0 mmol) ina mixture of EtOH (21 mL) and 2 M aqueous NaOH (34.9 mL, 69.9 mmol) washeated at reflux overnight. After cooling to room temperature, theethanol was removed under reduced pressure, and the aqueous residue wasdiluted with water. After adjustment of the pH to about 5 withconcentrated aqueous HCl, the mixture was stirred for 30 min and theprecipitate was collected by filtration and washed with water. Theresulting wet solid was dissolved in EtOAc, washed with brine, dried andconcentrated to provide 2-amino-4-bromo-5-methylbenzoic acid as a paleyellow solid (2.92 g, 91% yield). Mass spectrum m/z 212, 214 (M+H)⁺.

Intermediate 28D: 4-Bromo-2-hydrazinyl-5-methylbenzoic acidhydrochloride

A suspension of 2-amino-4-bromo-5-methylbenzoic acid (2.92 g, 12.7 mmol)in a mixture of 37% aqueous HCl (12.7 mL) and water (4.3 mL), cooled ina NaCl-ice bath, was treated slowly dropwise with a solution of sodiumnitrite (0.963 g, 14.0 mmol) in water (4.5 mL). The resulting mixturewas stirred for 45 min, then was treated slowly dropwise with a solutionof tin(II) chloride dihydrate (8.59 g, 38.1 mmol) in 37% aqueous HCl(8.2 mL). The cooling bath was removed, and the mixture was stirred atroom temperature for 60 min. The mixture was filtered, and the collectedprecipitate was washed with water and dried. The solid was trituratedand sonicated in MeOH, and the mixture was concentrated. The residue wastriturated and sonicated with DCM, and the precipitate was collected byfiltration and washed with DCM to give4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride as a white solid(2.17 g, 61% yield). Mass spectrum m/z 245, 247 (M+H)⁺.

Intermediate 28E:5-Bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid

A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride(2.17 g, 7.71 mmol), ethyl 3-oxocyclohexanecarboxylate (1.44 g, 8.48mmol) and acetic acid (1.32 mL, 23.1 mmol) in toluene (40 mL) was heatedin an oil bath at 117° C. for 5 h. The mixture was concentrated anddried under vacuum, and the residue was diluted with toluene (18 mL) andTFA (4.5 mL). The mixture was heated at 90° C. overnight. The cooledmixture was diluted with EtOAc, sonicated, and the precipitate wascollected by filtration and washed with EtOAc to give a yellow solid.The filtrate was concentrated and the residue was suspended in EtOAcwith sonication. The precipitate was collected by filtration andcombined with the first precipitate. The solid was triturated with MeOHto give5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid as a pale yellow solid (1.60 g, 55% yield). Mass spectrum m/z 380,382 (M+H)⁺.

Intermediate 28F:4-Bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid

A solution of5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid (1.60 g, 4.21 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2.10g, 9.26 mmol) in THF (45 mL) was heated at 60° C. for 60 min. The cooledmixture was diluted with EtOAc (about 70 mL), stirred for 15 min, andthe precipitate was collected by filtration, washed with EtOAc anddried. The filtrate was concentrated, and the residue was trituratedwith MeOH, filtered, and the collected precipitate was washed with MeOH.The two solids were combined to give4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid as apale yellow solid (1.40 g, 88% yield). Mass spectrum m/z 376, 378(M+H)⁺.

Intermediate 28G: Ethyl5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate

A mixture of4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid (1.40g, 3.72 mmol), EDC (1.070 g, 5.58 mmol), and HOBT (0.855 g, 5.58 mmol)in a mixture of THF (30 mL) and DCM (5 mL) was stirred at roomtemperature for 60 min. Ammonium hydroxide (0.217 mL, 5.58 mmol) wasadded, and the mixture was stirred at room temperature overnight. Themixture was diluted with EtOAc and washed with saturated aqueous NaHCO₃.Phase separation could not be achieved, so the mixture was filtered, andthe collected solid was washed sequentially with water and EtOAc,triturated with MeOH and dried. The EtOAc-water filtrate was separatedand the organic phase was washed with brine, dried and concentrated. Theresidue was triturated with MeOH, and the resulting solid was combinedwith the first solid to give ethyl5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate as an off-whitesolid (1.27 g, 91% yield). Mass spectrum m/z 375, 377 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.48 (d,J=0.9 Hz, 1H), 8.20 (br. s., 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.59(br. s., 1H), 4.37 (q, J=7.0 Hz, 2H), 2.55 (s, 3H), and 1.37 (t, J=7.0Hz, 3H).

Intermediate 28

A solution of ethyl5-bromo-8-carbamoyl-6-methyl-9H-carbazole-2-carboxylate (0.500 g, 1.33mmol) in THF (12 mL) at −78° C. was treated dropwise over 10 min with1.6 M methyllithium in ether (2.50 mL, 4.00 mmol). The mixture wasstirred at −78° C. for 30 min, then was treated with additionalmethyllithium solution (1.67 mL, 2.67 mmol). After 30 min more,additional methyllithium solution (1.67 mL, 2.67 mmol) was added andstirring was continued for 45 min. The mixture was then treated withsaturated aqueous NH₄Cl and allowed to warm to room temperature. Themixture was diluted with EtOAc and washed sequentially with water andbrine. The aqueous layers were extracted with EtOAc, and the combinedorganic layers were dried and concentrated to provide an off-whitesolid. The solid was triturated and sonicated with MeOH and collected byfiltration. The filtrate was purified by reverse-phase preparative HPLC.The appropriate fractions were treated with saturated aqueous NaHCO₃ andconcentrated. The residue was partitioned between EtOAc and water. Theorganic phase was washed with brine, and the aqueous layers wereextracted with EtOAc. The combined organic layers were dried andconcentrated, and the residue was combined with the first solid to give4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide asa tan solid (0.409 g, 85% yield). Mass spectrum m/z 343, 345 (M+H—H₂O)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.12(br. s., 1H), 7.91-7.89 (m, 2H), 7.48 (br. s., 1H), 7.36 (dd, J=8.3, 1.7Hz, 1H), 5.06 (s, 1H), 2.53 (s, 3H), and 1.51 (s, 6H).

Intermediate 295-Bromo-6-chloro-2-(RS)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(racemic mixture)

Intermediate 29A: 4-Bromo-5-chloro-2-hydrazinylbenzoic acidhydrochloride

A solution of sodium nitrite (3.03 g, 43.9 mmol) in water (14.8 mL) wasadded dropwise to a cooled (−10° C., NaCl-ice bath) suspension of2-amino-4-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in 37% aqueousHCl (39.9 mL) and water (13.3 mL), at such rate that the temperature didnot exceed 0° C. The resulting suspension was stirred at 0° C. for 15min, then was treated with a solution of tin(II) chloride hydrate (22.7g, 120 mmol) in 37% aqueous HCl (17 mL). The resulting mixture waswarmed to room temperature and stirred for 60 min. The precipitate wascollected by filtration, washed with water and air-dried overnight togive 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride as anoff-white solid (12.86 g, 96% yield). Mass spectrum m/z 365, 267 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (br. s., 1H), 7.95 (s, 1H), 7.55 (s,1H).

Intermediate 29B:5-Bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid

A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride(12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) washeated at 105° C. overnight. After 16 h, more acetic acid (6 mL) andethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixturewas heated at 110° C. for 4.5 h. The mixture was concentrated, and theresidue was combined with toluene (100 mL) and TFA (20 mL). Thesuspension was heated at 90° C. overnight. The cooled mixture wasconcentrated and the residue was suspended in EtOAc. The resulting solidwas collected by filtration, washed with EtOAc and air-dried to give5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (br. s., 1H), 11.24 (s, 1H),7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09(m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).

Intermediate 29C: Ethyl5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate

Following the procedure used to prepare Intermediate 24D,5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid was converted into ethyl5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylateas a light brown solid (8.54 g, 78% yield). Mass spectrum m/z 399, 401(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (br. s., 1H), 11.24 (s, 1H),7.69 (s, 1H), 4.12 (qd, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m,1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).

Intermediate 29

A solution of ethyl5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate(7.03 g, 17.6 mmol) in THF (200 mL) was cooled in a dry ice-acetone bathand treated portionwise over 40 min with 1.6 M methyllithium in THF(66.0 mL, 106 mmol). After 60 min, the mixture was treated slowly at−78° C. with saturated aqueous NH₄Cl and stirred for 10 min whilewarming to room temperature. The mixture was extracted 3 times with DCM,and the combined organic phases were washed sequentially with water andbrine, and dried and concentrated. The residue was purified by columnchromatography on silica gel (120 g), eluting with EtOAc-hexanes(gradient from 0-100%), to give5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamideas a yellow solid (4.66 g). Mass spectrum m/z 385, 387 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.13 (br. s., 1H), 7.76 (s, 1H),7.50 (br. s., 1H), 3.28 (d, J=5.5 Hz, 1H), 2.94 (dd, J=17.1, 4.7 Hz,1H), 2.79-2.66 (m, 1H), 2.49-2.39 (m, 1H), 2.14 (d, J=9.5 Hz, 1H), 1.66(td, J=11.4, 4.1 Hz, 1H), 1.33 (qd, J=12.4, 5.2 Hz, 1H), 1.15 (s, 6H).

Intermediates 30 and 31(R)-5-Bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(I-30), and(S)-5-Bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(I-31)

A sample of racemic5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate29] (2.35 g) was separated by chiral super-critical fluid chromatographyas follows: column: CHIRALPAK® IA (3×25 cm, 5 μm); Mobile Phase:CO₂-MeOH (50:50) at 124 mL/min, 100 bar, 45° C.; sample preparation: 39mg/mL in MeOH-DMSO (4:1); injection: 2.33 mL. The first peak elutingfrom the column provided the (R) isomer,(R)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate30] as a yellow solid (1.15 g). Mass spectrum m/z 385, 387 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.12 (br. s., 1H), 7.75 (s, 1H),7.57-7.45 (m, 1H), 4.23 (s, 1H), 3.27 (d, J=4.7 Hz, 1H), 2.93 (dd,J=17.2, 4.7 Hz, 1H), 2.78-2.67 (m, 1H), 2.48-2.39 (m, 1H), 2.16-2.08 (m,1H), 1.69-1.59 (m, 1H), 1.37-1.26 (m, 1H), 1.14 (s, 6H).

The second peak eluting from the column provided the (S) isomer,(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate 31] as an off-white solid (0.92 g). Mass spectrum m/z 385,387 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.12 (br. s.,1H), 7.74 (s, 1H), 7.49 (br. s., 1H), 4.23 (s, 1H), 3.27 (d, J=5.0 Hz,1H), 2.93 (dd, J=17.1, 4.6 Hz, 1H), 2.72 (t, J=11.8 Hz, 1H), 2.48-2.37(m, 1H), 2.12 (d, J=9.2 Hz, 1H), 1.69-1.59 (m, 1H), 1.38-1.24 (m, 1H),1.14 (s, 6H).

The absolute configuration of Intermediate 30 was confirmed by singlecrystal x-ray analysis of crystals prepared by dissolving the compoundin excess 1,2-dichloroethane/EtOAc/acetic acid and slowly evaporatingthe solvent at room temperature to provide a di-acetic acid solvate.Unit cell dimensions: a=11.690(2)Å, b=7.0901(9) Å, c=14.427(3)Å, α=90°,β=110.607(5)°, γ=90°, Volume=1119.2(3) Å³; Volume/Number of molecules inthe unit cell=560 Å³; Space group: P2₁; Molecules of Intermediate30/asymmetric unit (Z′): 1; Density, calc g-cm⁻³: 1.501. Fractionalatomic coordinates at room temperature are given in Table 8, and adepiction of the structure is given in FIG. 1.

TABLE 8 Fractional Atomic Coordinates for the Di-acetic Acid Solvate ofIntermediate 30 at Room Temperature Atom X Y Z Br1 0.7129 0.3740 0.6642Cl1 0.7740 0.3738 0.4607 N1 0.2665 0.3652 0.4430 O1 0.2004 0.3636 0.2416C1 0.1772 0.3609 0.5790 C2 0.5901 0.3791 0.5379 C3 0.2812 0.3738 0.5418C4 0.3773 0.3661 0.4329 C5 0.4669 0.3740 0.5291 C6 0.3082 0.3690 0.2482C7 0.5312 0.3740 0.3598 C8 0.4074 0.3753 0.3462 C9 0.4036 0.3762 0.5976C10 0.4463 0.3870 0.7085 C11 0.6203 0.3747 0.4534 C12 0.2289 0.31650.6913 N2 0.3387 0.3721 0.1672 O2 0.1932 0.2852 0.8423 C13 0.1290 0.32930.7384 C14 0.0723 0.5210 0.7302 C15 0.0325 0.1757 0.6967 C16 0.33890.4360 0.7413 O3 0.0996 0.3570 −0.0085 C17 0.0053 0.3621 0.0046 O4−0.0020 0.3642 0.0929 C18 −0.1174 0.3580 −0.0772 C19 0.6259 0.38100.0872 O5 0.5910 0.4309 0.1503 O6 0.7118 0.4731 0.0663 C20 0.5791 0.22000.0206 H1 0.1973 0.3602 0.3950 H2 0.1212 0.2621 0.5441 H3 0.1327 0.47930.5676 H4 0.5548 0.3721 0.3046 H5 0.5091 0.4833 0.7321 H6 0.4813 0.26740.7370 H7 0.2569 0.1852 0.6979 H8 0.2826 0.3705 0.1095 H9 0.4142 0.37550.1729 H10 0.1460 0.2951 0.8728 H11 0.0219 0.5258 0.7703 H12 0.02320.5455 0.6624 H13 0.1355 0.6145 0.7528 H14 0.0720 0.0559 0.7005 H15−0.0148 0.2037 0.6289 H16 −0.0205 0.1714 0.7347 H17 0.3637 0.4190 0.8124H18 0.3175 0.5675 0.7267 H19 0.0671 0.3654 0.1347 H20 −0.1430 0.4843−0.0980 H21 −0.1761 0.2992 −0.0536 H22 −0.1116 0.2873 −0.1321 H23 0.73790.5591 0.1062 H24 0.6424 0.1271 0.0321 H25 0.5538 0.2622 −0.0469 H260.5107 0.1656 0.0330

Intermediate 325-Methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3 (2H)-dione

Intermediate 32A: Ethyl 2-(3-methoxypyridin-2-yl)acetate

A stirred solution of diisopropylamine (0.385 mL, 2.70 mmol) in THF (2mL) at 0° C. was treated slowly with 1.6 M n-butyllithium in hexanes(1.69 mL, 2.70 mmol). The mixture was stirred for 15 min, then was addedover 5 min to a stirred solution of 3-methoxy-2-picoline (0.133 g, 1.08mmol) and diethyl carbonate (0.262 mL, 2.16 mmol) in THF (5 mL) at −78°C. After stirring for 45 min more, the cooling bath was removed andstirring was continued overnight at room temperature. The mixture wastreated with saturated aqueous NH₄Cl and diluted with EtOAc. The organicphase was separated, washed sequentially with saturated aqueous NaHCO₃and brine, and dried and concentrated. The residue was purified bycolumn chromatography on silica gel (12 g), eluting with 50%EtOAc-hexanes, to provide ethyl 2-(3-methoxypyridin-2-yl)acetate as anoil (0.17 g, 81% yield). Mass spectrum m/z 196 (M+H)⁺.

Intermediate 32B: Sodium 2-(3-methoxypyridin-2-yl)acetate

A stirred solution of ethyl 2-(3-methoxypyridin-2-yl)acetate (0.17 g,0.871 mmol) in THF (2.5 mL) at room temperature was treated with 3 Maqueous NaOH (0.581 mL, 1.74 mmol). After 7 h, the mixture wasconcentrated to remove the THF and the aqueous residue was frozen on dryice and lyophilized to provide sodium 2-(3-methoxypyridin-2-yl)acetateas a white solid. A quantitative yield was assumed and the material usedwithout further purification. Mass spectrum m/z 168 (M+H)⁺.

Intermediate 32C: N-(3-Bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide

A mixture of sodium 2-(3-methoxypyridin-2-yl)acetate (0.166 g, 0.871mmol), 3-bromo-2-methylaniline (0.118 mL, 0.958 mmol), DIEA (0.608 mL,3.48 mmol) and HATU (0.397 g, 1.05 mmol) in DMF (4.0 mL) was stirred atroom temperature. After 1 h, the mixture was diluted with EtOAc andwashed twice with 10% aqueous LiCl, then with brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel to provideN-(3-bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide as a paleyellow solid (0.213 g, 73% yield). Mass spectrum m/z 335, 337 (M+H)⁺.

Intermediate 32D:2-(3-Methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A mixture ofN-(3-bromo-2-methylphenyl)-2-(3-methoxypyridin-2-yl)acetamide (4.00 g,11.9 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.48 g,13.7 mmol) in DMSO (7 mL) and dioxane (35 mL) was bubbled with argon for5 min, then was treated with potassium acetate (2.93 g, 29.8 mmol).Bubbling was continued for 2 min, then the mixture was treated withPdCl₂(dppf) DCM adduct (0.487 g, 0.597 mmol). The reaction vessel wassealed and heated at 90° C. overnight. The cooled mixture was dilutedwith EtOAc and washed sequentially with water and brine. The combinedaqueous layers were extracted with EtOAc, and the combined organiclayers were dried and concentrated. The residue was filtered through aplug of silica gel with 60% EtOAc-hexanes, and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes, to give2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamideas a tan solid (5.1 g, 82% yield). ¹H NMR (400 MHz, chloroform-d) δ 9.65(br. s., 1H), 8.20 (dd, J=4.3, 1.7 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.54(d, J=7.3 Hz, 1H), 7.24-7.17 (m, 3H), 4.01 (s, 2H), 3.88 (s, 3H), 2.45(s, 3H), 1.35 (s, 12H).

Intermediate 32

A mixture of2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(1.45 g, 3.78 mmol) and CDI (2.45 g, 15.1 mmol) in toluene (19 mL) washeated at 110° C. for 3 h. The cooled mixture was partitioned betweenEtOAc and water. The organic layer was washed sequentially with waterand brine, dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes, to give5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dioneas a yellow solid (0.571 g, 37% yield). Mass spectrum m/z 409 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.0 Hz, 1H), 7.91 (dd, 1.2 Hz,1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (dd, J=7.8, 1.2 Hz, 1H), 6.39-6.30 (m,2H), 6.24 (s, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 1.34 (s, 12H).

Intermediate 335-Chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(racemic mixture)

Intermediate 33A: Diethyl 2-(3-chloropyridin-2-yl)malonate

A mixture of 3-chloro-2-fluoropyridine (5.00 g, 38.0 mmol), diethylmalonate (14.6 g, 91 mmol) and Cs₂CO₃ (29.7 g, 91 mmol) in DMSO (42 mL)was heated at 100° C. for 7 h. After stirring overnight at roomtemperature, the mixture was diluted with EtOAc, washed twice withwater, then with brine. The combined aqueous layers were extracted withEtOAc, and the combined organic phases were dried and concentrated togive crude diethyl 2-(3-chloropyridin-2-yl) malonate as a colorless oil,used without further purification. Mass spectrum m/z 272 (M+H)⁺.

Intermediate 33B: Ethyl 2-(3-chloropyridin-2-yl)acetate

A mixture of diethyl 2-(3-chloropyridin-2-yl) malonate (10.32 g, 38mmol), sodium chloride (5.55 g, 95 mmol) and water (3.42 mL, 190 mmol)in DMSO (40 mL) was heated at 145° C. for 8 h. The mixture was cooled toroom temperature, diluted with EtOAc and washed twice with water, thenwith brine. The organic phase was dried and concentrated to providecrude ethyl 2-(3-chloropyridin-2-yl)acetate, used without furtherpurification. Mass spectrum m/z 200 (M+H)⁺.

Intermediate 33C: Sodium 2-(3-chloropyridin-2-yl)acetate

A solution of ethyl 2-(3-chloropyridin-2-yl)acetate (7.59 g, 38 mmol) inTHF (76 mL) was treated at room temperature with 3 M aqueous NaOH (25.3mL, 76 mmol). The mixture was stirred at room temperature overnight andconcentrated to remove the THF. The aqueous residue was frozen on dryice and lyophilized to give sodium 2-(3-chloropyridin-2-yl)acetate as anoff-white solid, used without further purification. Mass spectrum m/z172 (M+H)⁺.

Intermediate 33D:N-(3-Bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide

A mixture of sodium 2-(3-chloropyridin-2-yl)acetate (7.39 g, 38 mmol),3-bromo-2-methylaniline (4.7 mL, 38.4 mmol), DIEA (13.3 mL, 76 mmol) andHATU (14.6 g, 38.4 mmol) in DMF (127 mL) was stirred at roomtemperature. After 90 min the mixture was diluted with EtOAc and washedtwice with 10% LiCl, then with brine. The combined aqueous layers wereextracted with EtOAc, and the combined organic phases were dried andconcentrated to a small volume. The solution was seeded with a crystalfrom an earlier batch and allowed to stand overnight to provide aprecipitate which was collected by filtration and washed with 50%EtOAc-hexanes to provide a white solid. The filtrate was concentratedand recrystallized similarly three times to provide additional solid.The solids were combined to giveN-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide as a whitesolid (11.43 g, 89% yield). Mass spectrum m/z 339, 341 (M+H)⁺. ¹H NMR(400 MHz, chloroform-d) δ 9.76 (br. s., 1H), 8.52 (d, J=3.5 Hz, 1H),7.92 (d, J=7.9 Hz, 1H), 7.80 (dd, J=8.1, 1.1 Hz, 1H), 7.36 (d, J=7.9 Hz,1H), 7.32-7.23 (m, 1H), 7.06 (t, J=8.0 Hz, 1H), 4.16 (s, 2H), 2.39 (s,3H).

Intermediate 33E:2-(3-Chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A mixture ofN-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide (4.0 g,11.78 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.29 g,12.96 mmol) in DMSO (5 mL) and dioxane (25 mL) was bubbled with argonfor 7 min, followed by addition of potassium acetate (2.89 g, 29.4mmol). Argon bubbling was continued for 7 min after which PdCl₂(dppf)DCM adduct (0.481 g, 0.589 mmol) was added. The mixture was heated at90° C. for 7 h. The cooled mixture was diluted with EtOAc and filteredthrough CELITE®. The filtrate was washed sequentially with water andbrine. The combined aqueous layers were extracted with EtOAc, and thecombined organic phases were dried and concentrated. The residue wasrecrystallized from EtOAc to provide a white solid. The mother liquorwas concentrated and the residue was recrystallized from EtOAc. The twosolids were combined to provide2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamideas a white solid (3.88 g, 85% yield). Mass spectrum m/z 387 (M+H)⁺.

Intermediate 33

A mixture of2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(0.192 g, 0.497 mmol) and CDI (0.322 g, 1.986 mmol) in toluene (2 mL)was heated at 110° C. After 5 h, the cooled mixture was diluted withEtOAc and washed sequentially with water and brine. The combined aqueouslayers were extracted with EtOAc, and the combined organic phases weredried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes, to provideracemic5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dioneas a bright yellow solid (0.133 g, 65% yield). Mass spectrum m/z 413(M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.26 (dt, J=7.6, 0.9 Hz, 1H),7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.27-7.18 (m, 2H),6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s, 3H), 1.36 (s, 12H).

Intermediates 34 and 35

5-Chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(I-34), and5-Chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(I-35)

A sample of racemic5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate33] was separated by chiral super-critical fluid chromatography asfollows: column: WHELK-O® R,R (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH(55:45) at 200 mL/min, 100 bar, 35° C.; sample preparation: 96 mg/mL inMeCN-DCM (1:4); injection: 5 mL. The first peak eluting from the columnprovided5-chloro-2-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 34]. The second peak eluting from the column provided5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate35]. The mass spectrum and ¹H NMR for each enantiomeric atropisomer werethe same as those for Intermediate 33.

Alternatively, a sample of racemic5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 33] was separated by chiral super-critical fluidchromatography as follows: column: WHELK-O® R,R (3×25 cm, 5 μm); MobilePhase: CO₂—CH₃CN (55:45) at 200 mL/min, 100 bar, 35° C.; samplepreparation: 96 mg/mL in MeCN-DCM (1:4); injection: 5 mL. The first peakeluting from the column provided5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate35]. The material could be further purified by dissolving in THF,diluting with hexanes and collecting the precipitate by filtration.

The absolute configuration of Intermediate 35 was confirmed by singlecrystal x-ray analysis of crystals prepared by dissolving the compoundin excess acetone and slowly evaporating the solvent at roomtemperature. Unit cell dimensions: a=19.6161(8) Å, b=9.1411(4) Å,c=12.7541(6) Å, α=90°, β=113.165(2°), γ=90°; Space group: C2; Moleculesof Intermediate 35/asymmetric unit (Z′): 1; Density, calc g-cm⁻³: 1.304.Fractional atomic coordinates at room temperature are given in Table 9,and a depiction of the structure is given in FIG. 2.

TABLE 9 Fractional Atomic Coordinates for Intermediate 35 at RoomTemperature Atom X Y Z Cl1 −0.1755 −0.1003 0.3365 O1 0.2261 0.69370.2037 C1 0.2132 0.8050 0.1156 C2 0.1347 0.7655 0.0313 O2 0.1028 0.69680.1045 B1 0.1597 0.6467 0.1980 C3 0.1403 0.4028 0.4772 C4 0.1906 0.51420.4966 C5 0.1012 0.4308 0.2727 C6 0.1966 0.5843 0.4048 C7 0.0966 0.36150.3668 C8 0.1517 0.5466 0.2926 C9 0.0863 0.8966 −0.0281 C10 0.05320.3809 0.1539 C11 0.1298 0.6565 −0.0585 C12 0.2226 0.9474 0.1724 C130.2710 0.7829 0.0643 N1 0.0457 0.2404 0.3528 C14 0.0746 0.1035 0.3564 N20.0270 −0.0148 0.3551 C15 −0.0287 0.2712 0.3397 C16 −0.0453 0.00860.3467 C17 −0.0720 0.1477 0.3375 C18 0.0561 −0.1540 0.3608 C19 −0.0563−0.2557 0.3562 C20 −0.0863 −0.1218 0.3472 C21 0.0166 −0.2724 0.3622 O3−0.0487 0.3988 0.3318 O4 0.1356 0.0809 0.3596 H1 0.1356 0.3551 0.5384 H20.2203 0.5422 0.5706 H3 0.2313 0.6587 0.4179 H4 0.0388 0.8624 −0.0807 H50.1101 0.9509 −0.0687 H6 0.0796 0.9586 0.0279 H7 0.0613 0.2788 0.1461 H80.0655 0.4356 0.0994 H9 0.0019 0.3967 0.1400 H10 0.1556 0.5689 −0.0231H11 0.1519 0.6967 −0.1073 H12 0.0787 0.6339 −0.1029 H13 0.1871 0.95710.2066 H14 0.2151 1.0241 0.1175 H15 0.2718 0.9545 0.2304 H16 0.31760.8231 0.1147 H17 0.2550 0.8312 −0.0083 H18 0.2769 0.6801 0.0543 H19−0.1208 0.1615 0.3296 H20 0.1039 −0.1652 0.3637 H21 −0.0838 −0.33780.3584 H22 0.0370 −0.3652 0.3671 — — — —

Intermediate 366-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione

Intermediate 36A: N-(3-Bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide

A mixture of 3-bromo-2-methylaniline (0.764 mL, 6.20 mmol),1,3-thiazol-2-ylacetic acid (0.74 g, 5.17 mmol) and DIEA (1.63 mL, 9.30mmol) in DMF (15 mL) was treated with HATU (2.36 g, 6.20 mmol). Afterstirring overnight, the mixture was diluted with EtOAc, washed twicewith 10% aqueous LiCl followed by brine, and the combined aqueous layerswere extracted with EtOAc. The combined organic layers were dried andconcentrated, and the residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes, to giveN-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide as a white solid(0.681 g, 42% yield). ¹H NMR (400 MHz, chloroform-d) δ 9.84-9.65 (m,1H), 7.91 (d, J=7.9 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.42-7.35 (m, 2H),7.07 (t, J=8.0 Hz, 1H), 4.18 (s, 2H), 2.38 (s, 3H).

Intermediate 36B:N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thiazol-2-yl)acetamide

A mixture of N-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide (0.53g, 1.70 mmol)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.476 g,1.87 mmol) and potassium acetate (0.418 g, 4.26 mmol) in DMSO (1.6 mL)and dioxane (8 mL) was bubbled with nitrogen for 5 min, followed by theaddition of PdCl₂(dppf) DCM adduct (0.070 g, 0.085 mmol). After bubblingwith nitrogen for another 5 min, the mixture was heated at 90° C. for 7h. The cooled mixture was diluted with EtOAc and filtered throughCELITE®. The filtrate was washed sequentially with water and brine, anddried and concentrated. The residue was purified by columnchromatography on silica gel (40 g), eluting with 50% EtOAc-hexanes, togiveN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thiazol-2-yl)acetamideas an off-white solid (0.45 g, 74% yield). Mass spectrum m/z 359 (M+H)⁺.

Intermediate 36

A mixture of N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thiazol-2-yl)acetamide (0.45 g, 1.26 mmol) and CDI (0.815 g,5.02 mmol) in toluene (6.5 mL) was heated at 110° C. for 2 h. The cooledmixture was partitioned between EtOAc and water. The organic layer waswashed with brine, and the combined aqueous layers were extracted withEtOAc. The combined organic layers were dried and concentrated. Theresidue was purified by column chromatography on silica gel (40 g),eluting with 70% EtOAc-hexanes, to give slightly impure6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dioneas a tan solid (34% yield). The material was used without furtherpurification. Mass spectrum m/z 385 (M+H)⁺.

Intermediate 37 Racemic5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione

Intermediate 37A: Diethyl 2-(3-fluoropyridin-2-yl)malonate

A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol), Cs₂CO₃ (13.59 g,41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) washeated at 100° C. for 4.5 h. The mixture was poured onto ice, dilutedwith EtOAc, and the organic phase was separated, washed sequentiallywith water and brine, and dried and concentrated. The residue waspurified by column chromatography on silica gel (80 g), eluting withEtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60%yield). ¹H NMR (400 MHz, chloroform-d) δ 8.42 (dt, J=4.6, 1.3 Hz, 1H),7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09(d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H).

Intermediate 37B: Ethyl 2-(3-fluoropyridin-2-yl)acetate

A mixture of diethyl 2-(3-fluoropyridin-2-yl)malonate (2.68 g, 10.5mmol), sodium chloride (0.675 g, 11.6 mmol) and water (0.378 mL, 21.0mmol) in DMSO (15 mL) was heated at 145° C. for 4.5 h. The mixture wascooled, diluted with EtOAc and washed sequentially with water and brine.The organic phase was dried and concentrated to provide ethyl2-(3-fluoropyridin-2-yl)acetate as a pale colored oil (1.90 g, 99%yield) which was used without further purification. Mass spectrum m/z184 (M+H)⁺.

Intermediate 37C: Sodium 2-(3-fluoropyridin-2-yl)acetate

A stirred solution of ethyl 2-(3-fluoropyridin-2-yl)acetate (1.90 g,10.4 mmol) in THF (26 mL) was treated with 3 M aqueous NaOH (6.9 mL,20.7 mmol) and stirred at room temperature overnight. The mixture wasconcentrated to remove the THF, and the residual aqueous solution wasfrozen and lyophilized to provide sodium 2-(3-fluoropyridin-2-yl)acetateas a white solid (assumed 100% yield), which was used without furtherpurification. Mass spectrum m/z 156 (M+H)⁺.

Intermediate 37D:N-(3-Bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide

A mixture of sodium 2-(3-fluoropyridin-2-yl)acetate (1.847 g, 10.37mmol), 3-bromo-2-methylaniline (1.41 mL, 11.4 mmol), DIEA (5.4 mL, 31.1mmol) and HATU (4.73 g, 12.4 mmol) in DMF (30 mL) was stirred at roomtemperature for 1.25 h. The mixture was diluted with EtOAc and washedtwice with 10% aqueous LiCl, then with brine. The combined aqueouslayers were extracted with EtOAc, and the combined organic phases weredried and concentrated. The residue was dissolved in hot EtOAc, allowedto cool, and the resulting white solid collected by filtration andwashed with 60% EtOAc-hexanes. The combined filtrates were concentratedand the residue was recrystallized twice using the same procedure. Theresidue from concentration of the final filtrate was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes, to provide asolid which was combined with the recrystallized batches to provideN-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide as a whitesolid (2.03 g, 61% yield). Mass spectrum m/z 323, 325 (M+H)⁺.

Intermediate 37E:2-(3-Fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A mixture ofN-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide (4.20 g,13.6 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.80 g,14.9 mmol) in dioxane (40 mL) was bubbled with nitrogen for 10 min.Potassium acetate (3.33 g, 34.0 mmol) was added to the mixture, bubblingwas continued for another 5 min, and PdCl₂(dppf) DCM adduct (0.555 g,0.679 mmol) was added. The mixture was heated at 100° C. overnight. Thecooled mixture was diluted with EtOAc, washed sequentially with waterand brine, dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with DCM-methyl t-butyl ether, toprovide2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamideas a white solid (3.80 g, 76% yield). Mass spectrum m/z 371 (M+H)⁺.

Intermediate 37

A mixture of2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(9.01 g, 24.3 mmol) and CDI (15.78 g, 97 mmol) in toluene (97 mL) washeated at 120° C. for 7 h. The cooled mixture was diluted with EtOAc andwashed sequentially with water and brine. The combined aqueous layerswere extracted with EtOAc, and the combined organic phases were driedand concentrated. The residue was purified by column chromatography onsilica gel (220 g), eluting with EtOAc-hexanes (gradient from 20-100%),to provide5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dioneas a yellow solid (6.26 g, 65% yield). Mass spectrum m/z 397 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 8.11 (dd, J=7.6, 0.8 Hz, 1H), 7.94 (dd,J=7.5, 1.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.8, 1.4 Hz,1H), 6.85-6.76 (m, 1H), 6.35 (td, J=7.4, 5.0 Hz, 1H), 6.09 (s, 1H), 2.36(s, 3H), 1.36 (s, 12H).

Intermediates 38 and 395-Fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(Single Atropisomers)

A sample of racemic5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate37] (7.5 g) was separated by chiral super-critical fluid chromatographyas follows: column: CHIRALCEL® OD-H (5×25 cm, 5 μm); Mobile Phase:CO₂-MeOH (76:24) at 280 mL/min, 100 bar, 40° C.; sample preparation:62.5 mg/mL in DCM-MeOH (1:1); injection: 0.83 mL. The first peak elutingfrom the column provided one atropisomer of5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate38] as a yellow solid (3.2 g, chiral purity 99.3%). The second peakeluting from the column provided the other atropisomer of5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate39] as a yellow solid (2.98 g, chiral purity 98.6%). The mass spectrumand ¹H NMR for both enantiomers were the same as those for Intermediate37.

Intermediate 40(Z)-4-((2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one

Intermediate 40A: N-(3-Bromo-2-chlorophenyl)-2-(methylamino)benzamide

A mixture of 3-bromo-2-chloroaniline [prepared according to theprocedure described in U.S. Pat. No. 8,242,260] (240 mg, 1.162 mmol) andtoluene (10 mL) at 0° C. was slowly treated with 2 M trimethylaluminumin toluene (0.99 mL, 1.98 mmol). The mixture was allowed to warm to roomtemperature and stirred for 15 min. A partial suspension of1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (300 mg, 1.52 mmol) intoluene (4 mL) was added slowly. The resulting mixture was heated at 50°C. for 4 h, cooled to 0° C., and treated dropwise with 1 M aqueous HCluntil no more gas evolution was observed. The mixture was stirred for 2h while warming to room temperature, then was extracted with EtOAc. Theorganic phase was washed sequentially with NaHCO₃ and brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-30%), toprovide N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide as a yellowsolid (110 mg, 28% yield). Mass spectrum m/z 339, 341 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 7.78 (dd, J=7.9, 1.5 Hz, 1H), 7.67(dd, J=8.1, 1.5 Hz, 1H), 7.57 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=1.3Hz, 1H), 7.38 (ddd, J=8.4, 7.1, 1.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H),6.70 (d, J=8.4 Hz, 1H), 6.68-6.61 (m, 1H), 2.79 (d, J=5.1 Hz, 3H).

Intermediate 40B:(Z)-4-((3-Bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one

A solution of N-(3-bromo-2-chlorophenyl)-2-(methylamino)benzamide (150mg, 0.442 mmol) in THF (15 mL) cooled to 0° C. and treated withtriphosgene (197 mg, 0.663 mmol). The mixture was stirred at roomtemperature for 1 h, then was cooled to 0° C. and treated with wateruntil gas evolution ceased. The mixture was concentrated, and theresidue was dissolved in EtOAc and washed sequentially with saturatedaqueous NaHCO₃, water and brine, dried and concentrated. The residue waspurified by column chromatography on silica gel, eluting withEtOAc-hexanes (gradient from 0-50%), to provide(Z)-4-((3-bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-oneas a beige solid (130 mg, 81% yield). ¹H NMR (400 MHz, chloroform-d) δ8.33 (dd, J=7.8, 1.4 Hz, 1H), 7.72-7.61 (m, 1H), 7.41 (dd, J=7.9, 1.5Hz, 1H), 7.36-7.28 (m, 1H), 7.16-7.08 (m, 2H), 7.07-7.01 (m, 1H), 3.55(s, 3H).

Intermediate 40

A mixture of(Z)-4-((3-bromo-2-chlorophenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one(130 mg, 0.356 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (117 mg,0.462 mmol) and potassium acetate (87 mg, 0.889 mmol) in dioxane (4 mL)was bubbled with nitrogen for 10 min. The mixture was treated withPdCl₂(dppf) DCM adduct (14.5 mg, 0.018 mmol), and heated at 90° C.overnight. The cooled mixture was partitioned between EtOAc and water.The organic phase was dried and concentrated and the residue waspurified by column chromatography on silica gel, eluting withEtOAc-hexanes (gradient from 0-50%), to provide(Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-oneas a yellow solid (120 mg, 82% yield). Mass spectrum m/z 413 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 8.40-8.30 (m, 1H), 7.67-7.58 (m, 1H),7.48-7.44 (m, 1H), 7.27 (s, 4H), 7.16-7.07 (m, 2H), 3.55-3.47 (m, 3H),1.40-1.37 (m, 12H).

Intermediate 413-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

Intermediate 41A: 2-Amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide

A mixture of 3-bromo-2-chloroaniline [prepared according to theprocedure described in U.S. Pat. No. 8,242,260] (600 mg, 2.91 mmol) andtoluene (10 mL) was cooled to 0° C. and slowly treated with 2 Mtrimethylaluminum in toluene (2.47 mL, 4.94 mmol). The mixture wasallowed to warm to room temperature and stirred for 15 min. The mixturewas treated with 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (684 mg,3.78 mmol) and heated at 50° C. for 16 h. The mixture was cooled to 0°C. and treated dropwise with 1 M aqueous HCl until gas evolutionstopped, and stirred for 2 h while allowing to warm to room temperature.The mixture was extracted three times with EtOAc. The combined organicphases were washed sequentially with saturated aqueous NaHCO₃ and brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 0-30%), to provide2-amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide as a pale yellowsolid (350 mg, 35% yield). Mass spectrum m/z 343, 345 (M+H)⁺. ¹H NMR(400 MHz, chloroform-d) δ 8.46 (dd, J=8.4, 1.3 Hz, 1H), 8.42 (br. s.,1H), 7.43 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (t,J=8.3 Hz, 1H), 7.15 (ddd, J=11.0, 8.0, 1.2 Hz, 1H), 6.69 (td, J=8.0, 5.1Hz, 1H), 5.72 (br. s., 2H).

Intermediate 41B:3-(3-Bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione

Triphosgene (453 mg, 1.53 mmol) was added in one portion to a solutionof amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide (350 mg, 1.019mmol) in THF (10 mL) at 0° C. The mixture was stirred at roomtemperature for 1 h, then was cooled to 0° C. and treated with wateruntil no more gas evolution was observed. The mixture was concentratedand the residue was dissolved in EtOAc, washed sequentially withsaturated aqueous NaHCO₃, water and brine, and dried and concentrated.The residue was purified by column chromatography on silica gel (24 g),eluting with EtOAc-hexanes (gradient from 0-50%), to provide3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as ayellow solid (320 mg, 85% yield). Mass spectrum m/z 369, 371 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 8.54 (br. s., 1H), 7.97 (d, J=8.1 Hz, 1H),7.77 (dd, J=6.8, 2.6 Hz, 1H), 7.46 (ddd, J=9.8, 8.3, 1.2 Hz, 1H),7.36-7.29 (m, 2H), 7.24 (td, 4.8 Hz, 1H).

Intermediate 41C:3-(3-Bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

Iodomethane (0.102 mL, 1.62 mmol) was added slowly to a mixture of3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (300 mg,0.812 mmol), DMF (5 mL) and Cs₂CO₃ (529 mg, 1.62 mmol). The mixture wasstirred at room temperature for 2 h, then was diluted with EtOAc, washedsequentially with water and brine, and dried and concentrated. Theresidue was purified by column chromatography on silica gel (24 g),eluting with EtOAc-hexanes (gradient from 0-30%), to provide3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dioneas a yellow solid (280 mg, 90% yield). Mass spectrum m/z 383, 385(M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.09 (dq, J=7.8, 0.8 Hz, 1H),7.79-7.71 (m, 1H), 7.49 (ddd, J=13.9, 8.1, 1.5 Hz, 1H), 7.32-7.29 (m,2H), 7.29-7.22 (m, 2H), 3.88 (s, 1.5H), 3.86 (s, 1.5H).

Intermediate 41

A mixture of3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione(150 mg, 0.391 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (129 mg,0.508 mmol), potassium acetate (96 mg, 0.978 mmol) and dioxane (8 mL)was bubbled with nitrogen for 10 min and treated with PdCl₂(dppf) DCMadduct (16 mg, 0.020 mmol). The mixture was heated at 90° C. for 16 h,then was cooled and partitioned between EtOAc and water. The organicphase was dried and concentrated, and the residue was purified by columnchromatography on silica gel (12 g), eluting with EtOAc-hexanes(gradient from 0-50%), to give3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dioneas a white glassy solid (52 mg, 31% yield). Mass spectrum m/z 431(M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.14-8.05 (m, 1H), 7.90-7.82(m, 1H), 7.51-7.35 (m, 3H), 7.26-7.19 (m, 1H), 3.86 (d, J=8.1 Hz, 3H),1.36 (s, 12H).

Intermediate 423-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione

A mixture of3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate 41B] (990 mg, 2.68 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (884 mg,3.48 mmol) and potassium acetate (657 mg, 6.70 mmol) in dioxane (8 mL)was bubbled with nitrogen for 10 min. PdCl₂(dppf) DCM adduct (109 mg,0.134 mmol) was added and the mixture was heated at 90° C. overnight.The cooled mixture was diluted with EtOAc, filtered, and the filtratewas concentrated. The residue was purified by column chromatography onsilica gel, eluting with MeOH-DCM (gradient from 0-5%), to give3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dioneas a brown solid (710 mg, 64% yield). Mass spectrum m/z 416 (M+H)⁺. ¹HNMR (400 MHz, chloroform-d) δ 8.55-8.38 (m, 1H), 8.06-7.93 (m, 1H),7.90-7.75 (m, 1H), 7.51-7.38 (m, 3H), 7.26-7.13 (m, 1H), 1.26 (br. s.,12H)

Intermediate 437-Fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione

Using the procedure used to prepare Intermediate 8,3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate15B] was converted into7-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione.Mass spectrum m/z 397 (M+H)⁺.

Intermediate 441-(4-Fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione

Intermediate 44A: Methyl3-(4-methoxybenzylamino)-2-(phenylselanyl)propanoate

A suspension of phenyl hypobromoselenoite (5.54 g, 23.5 mmol) andzinc(II) chloride (1.27 g, 9.29 mmol) in DCM (116 mL) was treated withmethyl acrylate (2.09 mL, 23.2 mmol). The mixture was stirred at roomtemperature for 30 min, then was treated with(4-methoxyphenyl)methanamine (6.4 mL, 48.8 mmol), forming a thicksuspension. After stirring for 16 h, the mixture was filtered, thecollected precipitate was washed with EtOAc, and the combined filtrateswere concentrated. The residue was purified by column chromatography onsilica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-50%), toprovide methyl 3-(4-methoxybenzylamino)-2-(phenylselanyl) propanoate asa light brown oil (3.68 g, 42% yield). Mass spectrum m/z 380 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 7.53-7.49 (m, 2H), 7.39-7.28 (m, 3H), 7.18 (d,J=8.6 Hz, 2H), 6.88-6.82 (m, 2H), 3.89 (dd, J=8.8, 5.9 Hz, 1H), 3.73 (s,3H), 3.61 (s, 2H), 3.55 (s, 3H), 2.93-2.78 (m, 2H).

Intermediate 44B: 1-Bromo-3-isocyanato-2-methylbenzene

A solution of triphosgene (2.25 g, 7.58 mmol) in toluene (27 mL), cooledin an ice-water bath, was treated slowly with a solution of3-bromo-2-methylaniline (3.00 g, 16.1 mmol) and DIEA (5.6 mL, 32.2 mmol)in toluene (5.4 mL). The resulting suspension was stirred at roomtemperature for 2 h. The precipitate was removed by filtration andwashed with EtOAc. The combined filtrates were diluted with EtOAc,washed with brine, dried and concentrated to provide1-bromo-3-isocyanato-2-methylbenzene as a brown oil (3.68 g, 98% yield),used without purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (dd, J=8.1,0.9 Hz, 1H), 7.31 (dd, J=7.9, 0.7 Hz, 1H), 7.15 (td, J=8.0, 0.7 Hz, 1H),2.38 (s, 3H).

Intermediate 44C:3-(3-Bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione

A mixture of methyl3-((4-methoxybenzyl)amino)-2-(phenylselanyl)propanoate (3.68 g, 9.73mmol), 1-bromo-3-isocyanato-2-methylbenzene (2.27 g, 10.7 mmol), andK₂CO₃ (0.672 g, 4.86 mmol) in DMF (49 mL) was heated at 65° C. for 5 h.The cooled mixture was partitioned between water and EtOAc. And theorganic phase was washed with brine, dried and concentrated to provide3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dioneas a light brown solid (5.43 g), used without further purification. Massspectrum m/z 557, 559, 561 (M+H)⁺.

Intermediate 44D:3-(3-Bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione(5.43 g, 9.73 mmol) in THF (97 mL) was treated with 30% aqueous hydrogenperoxide (5.0 mL, 48.6 mmol) and the mixture was stirred at roomtemperature for 30 min. Water was added and the mixture was extractedwith EtOAc. The organic phase was washed with brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (220 g), eluting with EtOAc-hexanes (gradient from 25-70%),to provide3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dioneas a white solid (2.10 g, 54% yield). Mass spectrum m/z 401, 403 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J=7.9 Hz, 1H), 7.70-7.65 (m, 1H),7.32-7.28 (m, 2H), 7.25-7.22 (m, 2H), 6.96-6.91 (m, 2H), 5.86 (d, J=7.9Hz, 1H), 4.89 (d, J=2.4 Hz, 2H), 3.74 (s, 3H), 2.02 (s, 3H).

Intermediate 44E: 3-(3-Bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione

A solution of3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione(0.87 g, 2.17 mmol) in TFA (5.5 mL) was treated withtrifluoromethanesulfonic acid (0.55 mL) and the mixture was stirred atroom temperature overnight. The mixture was slowly poured onto ice andstirred while warming to room temperature. The precipitate was collectedby filtration, washed with water and dried to provide3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione as a purple solid(0.62 g, 96% yield). Mass spectrum m/z 281, 283 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.36 (d, J=4.4 Hz, 1H), 7.67 (dd, J=6.5, 2.8 Hz, 1H), 7.60(dd, 5.9 Hz, 1H), 7.27-7.21 (m, 2H), 5.72 (dd, J=7.7, 1.3 Hz, 1H), 2.07(s, 3H).

Intermediate 44F:3-(3-Bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione

A stirred suspension of copper(II) acetate (0.543 g, 2.99 mmol),3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione (0.42 g, 1.49mmol), (4-fluorophenyl) boronic acid (0.418 g, 2.99 mmol), and activatedmolecular sieves (750 mg) in dry DCM (25 mL) was treated with pyridine(0.363 mL, 4.48 mmol) and stirred at room temperature overnight. Themixture was diluted with DCM, filtered through CELITE®, and the solidswere washed with DCM and THF. The combined filtrates were washed withwater, dried and concentrated. The residue was purified by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 20-40%), to give3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dioneas a yellow glassy solid (0.36 g, 43% yield). Mass spectrum m/z 375, 377(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (d, J=7.9 Hz, 1H), 7.68 (dd,J=7.9, 1.3 Hz, 1H), 7.60-7.51 (m, 2H), 7.40-7.22 (m, 4H), 5.95 (d, J=7.9Hz, 1H), 2.21-2.12 (m, 3H).

Intermediate 44

A mixture of3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione(250 mg, 0.666 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (186 mg,0.733 mmol), potassium acetate (131 mg, 1.33 mmol), and PdCl₂(dppf) DCMadduct (16 mg, 0.020 mmol) in dioxane (4.4 mL) was heated at 110° C.After 3 h, additional PdCl₂(dppf) DCM adduct was added and the mixturewas heated at 110° C. for 6 h more. The cooled mixture was diluted withEtOAc, filtered through CELITE® and the solids were washed with EtOAc.The combined filtrates were washed sequentially with saturated aqueousNaHCO₃ and brine, and dried and concentrated. The residue was purifiedby column chromatography on silica gel (24 g), eluting withEtOAc-hexanes (gradient from 25-100%), to give impure1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione as a yellow glassy solid (217 mg), usedwithout further purification. Mass spectrum m/z 423 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 7.90 (d, J=7.9 Hz, 1H), 7.69 (dd, J=7.0, 1.8 Hz, 1H),7.61-7.52 (m, 2H), 7.40-7.26 (m, 4H), 5.94 (d, J=7.9 Hz, 1H), 2.24 (s,3H), 1.32 (s, 12H).

Intermediate 454-Bromo-3-fluoro-7-(2-hydroxyethyl)-9H-carbazole-1-carboxamide

Intermediate 45A: Diethyl 2-(3-oxocyclohexyl)malonate

A solution of cyclohex-2-enone (3.05 mL, 30 mmol) and diethyl malonate(4.58 mL, 30.0 mmol) in THF (30 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (4.52 mL, 30.0 mmol) and heated at50° C. for 16 h. The cooled mixture was poured into EtOAc and washedsequentially with 1 M aqueous HCl and brine. The combined aqueous layerswere extracted with EtOAc, and the combined organic phases were driedand concentrated to give diethyl 2-(3-oxocyclohexyl)malonate as an oil(8.0 g), used without further purification. Mass spectrum m/z 257(M+H)⁺.

Intermediate 45B:5-Bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid

A solution of diethyl 2-(3-oxocyclohexyl)malonate (15.26 g, 59.5 mmol)and 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride[Intermediate24B] (17.0 g, 59.5 mmol) in acetic acid (120 mL) was heated at refluxfor 2 h, then was stirred overnight at room temperature. The precipitatewhich formed was collected by filtration to provide a white solid. Thefiltrate was concentrated and purified by column chromatography onsilica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-100%).The resulting oily product was crystallized from a mixture of EtOAc,ether and hexanes to provide additional solid, which was combined withthe first solid to provide5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid as a white solid (10.5 g, 49% yield). Mass spectrum m/z 470, 472(M+H)⁺.

Intermediate 45C: Diethyl2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malonate

A mixture of5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylicacid (0.981 g, 2.09 mmol), EDC (0.600 g, 3.13 mmol) and HOBT (0.383 g,2.50 mmol) in THF (5 mL) was stirred at room temperature for 60 min. Themixture was treated with NH₄OH (1.74 mL, 12.5 mmol) and stirred at roomtemperature overnight. The mixture was diluted with EtOAc, washedsequentially with saturated aqueous Na₂CO₃ and brine. The combinedaqueous layers were extracted with EtOAc, and the combined organicphases were dried and concentrated. The residue was purified by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 0-100%), to provide diethyl2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malonateas a slightly yellow solid (440 mg, 45% yield). Mass spectrum m/z 469,471 (M+H)⁺.

Intermediate 45D: Diethyl2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)malonate

A solution of diethyl2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malonate(2.26 g, 4.82 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2.30 g,10.1 mmol) in THF (30 mL) was heated at reflux for 3 h. The cooledmixture was diluted with EtOAc and washed sequentially with saturatedaqueous Na₂CO₃ and brine. The combined aqueous layers were extractedwith EtOAc, and the combined organic phases were dried and partiallyconcentrated. A white solid which formed was collected by filtration.The filtrate was passed through a pad of silica gel, eluting with EtOAc,and the effluent was concentrated to provide additional solid. The twosolids were combined to provide diethyl2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl) malonate as a whitesolid (1.86 g, 83% yield). Mass spectrum m/z 465, 467 (M+H)⁺.

Intermediate 45E: Ethyl2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate

A mixture of diethyl 2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)malonate (1.30 g, 2.80 mmol), sodium chloride (0.28 g, 7.01 mmol) andwater (0.25 mL, 14.01 mmol) in DMSO (6 mL) was heated at 150° C. for 20h. The cooled mixture was poured into water, forming a precipitate. Theprecipitate was collected by filtration and dried, then was trituratedwith DCM. The solid was collected by filtration and dried to provideethyl 2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate as a graysolid (930 mg, 84% yield). Mass spectrum m/z 393, 395 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 8.25 (br.s., 1H), 8.00 (d, J=10.1 Hz, 1H), 7.72 (s, 1H), 7.69 (br. s., 1H), 7.19(dd, J=8.4, 1.5 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.82 (s, 2H), 1.21 (t,J=7.2 Hz, 3H).

Intermediate 45

A solution of ethyl2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate (500 mg, 1.27mmol) in THF (10 mL) was treated with lithium borohydride (139 mg, 6.36mmol) and stirred at room temperature overnight. The mixture was treatedwith saturated aqueous NH₄Cl and stirred for 15 min. The mixture wasdiluted with water and extracted twice with EtOAc. The combined organicphases were dried and concentrated, and the residue was purified bycolumn chromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 30-100%), to provide4-bromo-3-fluoro-7-(2-hydroxyethyl)-9H-carbazole-1-carboxamide as awhite solid (310 mg, 69% yield). Mass spectrum m/z 351, 353 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.24(br. s., 1H), 7.98 (d, J=10.3 Hz, 1H), 7.72-7.63 (m, 2H), 7.15 (dd,J=8.4, 1.3 Hz, 1H), 4.68 (t, J=5.3 Hz, 1H), 3.73-3.64 (m, 2H), 2.90 (t,J=7.0 Hz, 2H).

Examples 1 and 23-Chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(1), and3-Chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(2)

Preparation 1A:3-Chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (100 mg, 0.262 mmol),8-fluoro-1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 2] (161 mg, 0.393 mmol),tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) and 2 Maqueous K₃PO₄ (0.26 mL, 0.524 mmol) in THF (2 mL) in a pressure reactionvial was heated at 90° C. for 2.5 h. The cooled mixture wasconcentrated, and the residue was purified by column chromatography onsilica gel (40 g), eluting with DCM-MeOH—NH₄OH (gradient from90:9:1-97:2.7:0.3). The resulting impure product was again purified bycolumn chromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 50-100%), to give3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (110 mg, 68% yield).Mass spectrum m/z 567 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 10.46(s, 1H), 8.17-8.10 (m, 1H), 7.76 (s, 1H), 7.69 (d, J=1.1 Hz, 1H),7.59-7.53 (m, 1H), 7.48 (ddt, J=13.9, 8.1, 1.8 Hz, 1H), 7.39 (dd,J=12.4, 7.8 Hz, 2H), 7.28-7.19 (m, 2H), 6.97 (t, J=8.5 Hz, 1H),3.87-3.93 (m, 3H), 1.87 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).

Examples 1 and 2

A sample of the mixture of four atropisomers of3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(90 mg) was separated by chiral super-critical fluid chromatography asfollows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-IPA(55:45) at 120 mL/min; sample preparation: 10 mg/mL; injection: 1 mL.The second peak eluting from the column provided3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 1] as a white solid. The isomeric purity was determined to be97.7%. Mass spectrum m/z 567 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d)δ 10.46 (s, 1H), 8.15 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=1.1Hz, 1H), 7.59-7.54 (m, 1H), 7.49 (ddd, J=13.9, 8.0, 1.7 Hz, 1H),7.43-7.36 (m, 2H), 7.28-7.19 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.89 (d,J=7.9 Hz, 3H), 1.88 (s, 3H), 1.65 (s, 6H).

The fourth peak eluting from the column provided3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 2] as a white solid. The isomeric purity was determined to be99.5%. Mass spectrum m/z 567 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d)δ 10.46 (s, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J=1.3Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddd, J=13.9, 8.0, 1.7 Hz, 1H), 7.39(dd, J=11.1, 7.8 Hz, 2H), 7.27-7.21 (m, 2H), 6.99 (d, J=8.4 Hz, 1H),3.91 (d, J=7.9 Hz, 3H), 1.88 (s, 3H), 1.66 (s, 6H).

The absolute configuration of Example 2 was confirmed by single crystalx-ray analysis of crystals prepared by dissolving the compound in excessmethanol and slowly evaporating the solvent at room temperature toprovide a methanol solvate (crystalline form M-1). Unit cell dimensions:a=9.75 Å, b=14.21 Å, c=21.26 Å, α=90.0°, β=90.0°, γ=90.0°; Space group:P2₁2₁2₁; Molecules of Example 2/asymmetric unit: 1; Volume/Number ofmolecules in the unit cell=736 Å³; Density (calculated)=1.391 g/cm³.Fractional atomic coordinates at 203 K are given in Table 2, and adepiction of the structure is given in FIG. 3.

Example 33-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide(single atropisomer)

Preparation 3A:3-Chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide(mixture of four atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (100 mg, 0.262 mmol),1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 4] (154 mg, 0.393 mmol), 2 M aqueous K₃PO₄ (0.26 mL, 0.524mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) inTHF (2 mL) in a pressure reaction vial was heated at 90° C. for 4 h. Thecooled mixture was concentrated and the residue was purified by columnchromatography on silica gel (40 g), eluting with DCM:MeOH:NH₄OH(gradient from 90:9:1-97:2.7:0.3). The resulting impure product wasagain purified by column chromatography on silica gel (40 g), elutingwith EtOAc-hexanes (gradient from 50-100%), to give3-chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide (mixture of fouratropisomers) as a white solid (105 mg, 68% yield). Mass spectrum m/z549 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.33(ddd, J=11.8, 7.9, 1.4 Hz, 1H), 7.80-7.74 (m, 2H), 7.69 (t, J=1.7 Hz,1H), 7.58-7.52 (m, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.38-7.30 (m, 3H), 7.24(ddd, J=13.9, 8.4, 1.7 Hz, 1H), 6.98 (dd, J=12.8, 8.4 Hz, 1H), 3.67-3.76(m, 3H), 1.88 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).

Example 3

A sample of the mixture of four atropisomers of3-chloro-7-(2-hydroxypropan-2-yl)-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamidewas separated by chiral super-critical fluid chromatography as follows:column: CHIRALPAK® IB (2×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (65:35) at55 mL/min. The third peak eluting from the column provided a singleatropisomer of3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamideas a white solid. The chiral purity was determined to be 97.7%. Massspectrum m/z 549 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 10.45 (s,1H), 8.32 (dd, J=8.0, 1.7 Hz, 1H), 7.80-7.73 (m, 2H), 7.69 (d, J=1.1 Hz,1H), 7.59-7.53 (m, 1H), 7.44-7.31 (m, 4H), 7.26 (dd, J=8.4, 1.5 Hz, 1H),7.01 (d, J=8.4 Hz, 1H), 3.72 (s, 3H), 1.89 (s, 3H), 1.66 (s, 6H)

Example 43-Chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

Preparation 4A:3-Chloro-4-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (100 mg, 0.262 mmol),1,8-dimethyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 9] (138 mg, 0.341 mmol), Cs₂CO₃ (171 mg, 0.524 mmol) andPdCl₂(dppf) DCM adduct (10.7 mg, 0.013 mmol) in THF (2 mL) and water(500 μl) was heated at 60° C. for 18 h. The cooled mixture wasconcentrated, and the residue was purified by column chromatography onsilica gel (40 g), eluting with EtOAc-hexanes (gradient from 30-100%),to give3-chloro-4-(RS)-(3-(RS)-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a light yellow solid (97 mg, 57%yield). Mass spectrum m/z 563 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d)δ 10.45 (s, 1H), 8.21-8.15 (m, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.69 (d,J=1.5 Hz, 1H), 7.59-7.51 (m, 2H), 7.44-7.40 (m, 1H), 7.36 (dd, J=7.7,1.1 Hz, 1H), 7.26-7.19 (m, 2H), 6.98 (t, J=7.9 Hz, 1H), 3.80 (d, J=9.9Hz, 3H), 2.70 (d, J=5.7 Hz, 3H), 1.88 (s, 3H), 1.64-1.66 (m, 6H).

Example 4

A sample of the mixture of four atropisomers of3-chloro-4-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(90 mg) was separated by chiral super-critical fluid chromatography asfollows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-IPA(55:45) at 85 mL/min; sample preparation: 18 mg/mL in MeOH; injection:2.5 mL. The fourth peak eluting from the column provided a singleatropisomer of3-chloro-4-(R)-(3-(1,8-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a white solid (17 mg). The chiral purity was determined to be greaterthan 99%. Mass spectrum m/z 563 (M+H—H₂O)⁺. ¹H NMR (400 MHz,chloroform-d) δ 10.45 (s, 1H), 8.17 (dd, J=7.8, 1.2 Hz, 1H), 7.75 (s,1H), 7.69 (d, J=1.1 Hz, 1H), 7.58-7.51 (m, 2H), 7.42 (dd, J=7.9, 1.1 Hz,1H), 7.36 (dd, J=7.7, 1.1 Hz, 1H), 7.27-7.19 (m, 2H), 6.99 (d, J=8.4 Hz,1H), 3.81 (s, 3H), 2.71 (s, 3H), 1.87 (s, 3H), 1.65 (s, 6H).

Examples 5 and 63-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(R)-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide, and3-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(S)-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide (SingleAtropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (200 mg, 0.524 mmol),7-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 14] (221 mg, 0.524 mmol), Cs₂CO₃ (512 mg, 1.57 mmol) andPdCl₂(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water(0.50 mL) was heated at 60° C. overnight, then at 90° C. for 4 h. Thecooled mixture was concentrated, and the residue was purified by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 50-100%), to give3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) (164 mg, 92% yield). This material wasseparated by chiral super-critical fluid chromatography as follows:column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-IPA (60:40)at 85 mL/min; sample preparation: 20.3 mg/mL in MeOH; injection: 0.75mL.

The third peak eluting from the column provided a single atropisomer of3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide[Example 5] (14 mg). The chiral purity was determined to be greater than99%. Mass spectrum m/z 579 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ10.43 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=1.1 Hz,1H), 7.55-7.49 (m, 1H), 7.44-7.34 (m, 1H), 7.35-7.31 (m, 1H), 7.19 (dd,J=8.5, 1.7 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.8, 2.2 Hz,1H), 6.69 (d, J=2.2 Hz, 1H), 3.95 (s, 3H), 3.63 (s, 3H), 1.85 (s, 3H),1.62 (s, 6H).

The fourth peak eluting from the column provided the other singleatropisomer3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(7-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide[Example 6] (28 mg). The chiral purity was determined to be greater than99%. Mass spectrum m/z 579 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ10.41 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=1.1 Hz,1H), 7.55-7.49 (m, 1H), 7.41-7.36 (m, 1H), 7.35-7.31 (m, 1H), 7.22 (dd,J=8.4, 1.5 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.84 (dd, J=9.0, 2.2 Hz,1H), 6.70 (d, J=2.2 Hz, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 1.85 (s, 3H),1.63 (s, 6H).

Example 73-Chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3](200 mg, 0.524 mmol),8-methoxy-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 12] (221 mg, 0.524 mmol), Cs₂CO₃ (512 mg, 1.57 mmol)PdCl₂(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water(0.50 mL) in a pressure reaction vial was heated at 60° C. overnight,then at 90° C. for 4 hours. The cooled mixture was diluted with DCM andMeOH, and concentrated. The residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 20-55%), to give a mixture of four atropisomers of3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(136 mg, 41% yield). This material was separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AD-H(3×25 cm, 5 μm); Mobile Phase: CO₂-IPA (55:45) at 85 mL/min; samplepreparation: 17 mg/mL in MeOH; injection: 1.0 mL. The fourth peakeluting from the column provided a single atropisomer of3-chloro-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-methoxy-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(26 mg, 20% yield). The chiral purity was determined to be greater than99%. Mass spectrum m/z 579 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ10.42 (s, 1H), 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.71 (s, 1H), 7.66 (d,J=1.1 Hz, 1H), 7.55-7.49 (m, 1H), 7.40-7.36 (m, 1H), 7.35-7.31 (m, 1H),7.25-7.19 (m, 3H), 6.97 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H),1.85 (s, 3H), 1.63 (s, 6H).

Example 83-Chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (200 mg, 0.524 mmol),6-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 13] (215 mg, 0.524 mmol), Cs₂CO₃ (512 mg, 1.57 mmol) andPdCl₂(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water (1mL) was heated at 60° C. overnight, then at 90° C. for 4 h. The cooledmixture was concentrated and the residue was purified twice by columnchromatography on silica gel (40 g), eluting with EtOAc-hexanes(gradient from 50-100%), to give a mixture of four atropisomers of3-chloro-4-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(129 mg, 39% yield). This material was separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AD-H(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH-MeCN (65:17.5:17.5) at 85mL/min; sample preparation: 15.4 mg/mL in MeOH; injection: 0.5 mL. Thethird peak eluting from the column provided a single atropisomer of3-chloro-4-(R)-(3-(6-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(33 mg). The isomeric purity was determined to be greater than 98%. Massspectrum m/z 567 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 10.44 (br.s., 1H), 8.29 (dd, J=8.1, 6.4 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H),7.56-7.49 (m, 1H), 7.36 (dd, J=15.2, 7.3 Hz, 2H), 7.22 (d, J=6.8 Hz,1H), 7.04-6.92 (m, 3H), 3.65 (s, 3H), 1.84 (s, 3H), 1.63 (s, 6H).

Example 93-Chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (200 mg, 0.524 mmol),7-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 15] (215 mg, 0.524 mmol), Cs₂CO₃ (512 mg, 1.57 mmol) andPdCl₂(dppf) DCM adduct (21.4 mg, 0.026 mmol) in THF (3 mL) and water(0.50 mL) was heated at 90° C. for 4 h. The cooled mixture wasconcentrated, and the residue was purified by column chromatography onsilica gel (220 g), eluting with EtOAc-hexanes (gradient from 0-40%), toprovide a mixture of four atropisomers of3-chloro-4-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(164 mg, 53% yield). The material was separated by chiral super-criticalfluid chromatography as follows: column: Lux Cel2 (3×25 cm, 5 μm);Mobile Phase: CO₂-MeOH-MeCN (62:19:19) at 85 mL/min; sample preparation:30 mg/mL in MeOH; injection: 0.5 mL. The material isolated from thethird peak eluting from the column was again separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AS(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH-MeCN (68:16:16) at 85 mL/min;sample preparation: 11.4 mg/mL in MeOH; injection: 3.5 mL. The firstpeak eluting from the column provided a single atropisomer of3-chloro-4-(R)-(3-(7-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a white solid (25 mg, 15% yield). The isomeric purity was determinedto be greater than 98%. Mass spectrum m/z 567 (M+H—H₂O)⁺. ¹H NMR (400MHz, chloroform-d) δ 10.46 (s, 1H), 8.31 (dd, J=8.6, 6.2 Hz, 1H), 7.76(s, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.38 (ddd, J=14.1,7.8, 1.0 Hz, 2H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 7.06-6.95 (m, 3H), 3.67(s, 4H), 1.86 (s, 3H), 1.65 (s, 6H).

Example 103-Chloro-4-(RS)-(3-(RS)-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (10 mg, 0.026 mmol),6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate16] (14.1 mg, 0.034 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium(II) chloride (12.8 mg, 0.020 mmol) and THF (2 mL) in areaction vial was treated with 2 M aqueous K₃PO₄ (0.039 mL, 0.079 mmol).The vial was sealed and subjected to three evacuate-fill cycles withnitrogen. The mixture was stirred at room temperature overnight. Thephases of the mixture were separated, the aqueous phase was extractedtwice with EtOAc, and the combined organic phases were dried andconcentrated. The residue was purified by column chromatography onsilica gel (40 g), eluting with EtOAc-hexanes (gradient from 80-100%).The isolated material was triturated with MeOH to give a solid afterfiltration. The filtrate was concentrated and subjected to columnchromatography on silica (40 g), eluting with DCM-MeOH—NH₄OH (gradientfrom 90:9:1-97:2.7:0.3) to give additional solid. The two solids werecombined to provide3-chloro-4-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a pale yellow solid (164 mg, 71%yield). Mass spectrum m/z 571 (M+H—H₂O)⁺. ¹H NMR (500 MHz, MeOH-d₄) δ8.04 (d, J=2.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.65 (dd, J=7.2, 3.2 Hz, 1H),7.57-7.52 (m, 1H), 7.43-7.34 (m, 3H), 7.18-7.07 (m, 1H), 6.90 (dd,J=8.4, 3.0 Hz, 1H), 1.84 (s, 3H), 1.62-1.56 (m, 6H).

Example 113-Chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A solution of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (3.08 g, 8.07 mmol) and8-fluoro-1-methyl(d₃)-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 21] (4.00 g, 9.68 mmol) in THF (33 mL) was treated with 2M aqueous K₃PO₄ (8.25 mL, 16.5 mmol). The mixture was bubbled with argonfor ca. 4 min while agitating on an ultrasonic bath, then was treatedwith 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride(447 mg, 0.686 mmol). The reaction vessel was sealed and subjected tosix evacuate-fill cycles with argon. The mixture was stirred at 50° C.for 16.5 h, then was cooled to room temperature. The mixture was dilutedwith EtOAc and washed with water. The aqueous phase was extracted twicewith EtOAc and the combined organic phases were washed with brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (330 g), eluting with EtOAc-hexanes (gradient from 40-100%),to provide3-chloro-4-(3-(S)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two diastereomers) as a light yellow-tan solid (3.877 g, 78%yield).

Material prepared by this method (5.01 g) was separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AS-H(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (70:30) at 160 mL/min, 40° C.;sample preparation: 22.75 mg/mL in 2:1 MeOH-dichloromethane; injection:1.4 mL. Pooled fractions containing the first peak eluting from thecolumn were concentrated, and the residue was sonicated in a smallamount of methanol. The precipitate was collected by filtration, rinsedwith methanol and dried to provide3-chloro-4-(R)-(3-(S)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a white solid (2.029 g). Mass spectrum m/z 570 (M+H—H₂O)⁺, 610(M+Na)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.12-8.03 (m, 2H), 7.74 (d, J=1.1Hz, 1H), 7.67-7.53 (m, 2H), 7.46 (dd, J=7.9, 1.1 Hz, 1H), 7.39-7.29 (m,2H), 7.17 (dd, J=8.5, 1.7 Hz, 1H), 6.96-6.87 (m, 1H), 1.81 (s, 3H), 1.61(d, J=1.3 Hz, 6H). [α]D: +85.1° (c 2.38, CHCl₃). DSC melting point onsettemperature=255.6° C. (heating rate=10° C./min.).

The absolute configuration of Example 11 was confirmed by single crystalx-ray analysis of crystals prepared by dissolving the compound in 1:1:1methanol/acetonitrile/acetone and slowly evaporating the solvent at roomtemperature to provide a methanol solvate (crystalline form M-1). Unitcell dimensions: a=9.78 Å, b=14.26 Å, c=21.38 Å, α=90.0°, β=90.0°,γ=90.0°; Space group: P2₁2₁2₁; Molecules of Example 11/asymmetric unit:1; Volume/Number of molecules in the unit cell=746 Å³; Density(calculated)=1.381 g/cm³. Fractional atomic coordinates at roomtemperature are given in Table 5, and a depiction of the structure isgiven in FIG. 4. The absolute configuration was further confirmed bysingle crystal x-ray analysis of crystals prepared by dissolving Example11 in excess aqueous acetone and slowly evaporating the solvent at roomtemperature to provide a monohydrate (crystalline form H-1). Unit celldimensions: a=9.41 Å, b=14.51 Å, c=21.12 Å, α=90.0°, β=90.0°, γ=90.0°;Space group: P2₁2₁2₁; Molecules of Example 11/asymmetric unit: 1;Volume/Number of molecules in the unit cell=721 Å³; Density(calculated)=1.396 g/cm³. Fractional atomic coordinates at roomtemperature are given in Table 3.

Example 123-Chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (76 mg, 0.20 mmol),8-fluoro-1-methyl(d₃)-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 22] (75 mg, 0.18 mmol), andCs₂CO₃ (118 mg, 0.363 mmol) in THF (1.6 mL) and water (0.40 mL) in avial was bubbled with argon for 1 min with sonication. The mixture wastreated with PdCl₂(dppf) DCM adduct (7.4 mg, 0.009 mmol) and the vialwas sealed and heated at 45° C. for 19 h. The cooled mixture was dilutedwith EtOAc and water. The layers were separated and the aqueous layerwas extracted again with EtOAc. The combined organic layers were washedwith brine, dried and concentrated. The residue was subjected to columnchromatography on silica gel (12 g), eluting with EtOAc-hexanes(gradient from 60%-100%). The resulting impure product was purified byreverse phase HPLC (Luna Axia 5μ C₁₈ 30×100 mm), eluting with MeCN-watercontaining 0.1% TFA (gradient from 10-100%, 30 mL/min). The appropriatefractions were treated with saturated aqueous NaHCO₃ and concentrated toan aqueous suspension. The precipitate was collected by filtration,washed with water and dried under vacuum to provide a mixture of twoatropisomers of3-chloro-4-(3-(R)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a white solid (60.9 mg, 57% yield). This material was separated bychiral super-critical fluid chromatography as follows: column:CHIRALPAK® AD-H (5×25 cm, 5 μm); Mobile Phase: CO₂-IPA (60:40) at 250mL/min, 35° C.; sample preparation: 7.5 mg/mL in MeOH; injection: 2.5mL. The residue obtained from concentration of the second peak elutingfrom the column was further purified by column chromatography on silicagel (4 g), eluting with EtOAc-hexanes (gradient from 40%-100%), toprovide3-chloro-4-(R)-(3-(R)-(8-fluoro-1-methyl(d₃)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a white solid (19.7 mg, 68% yield). Mass spectrum m/z 570 (M+H—H₂O)⁺,610 (M+Na)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.11-8.04 (m, 2H), 7.74 (d,J=1.1 Hz, 1H), 7.66-7.53 (m, 2H), 7.46 (dd, J=7.9, 1.1 Hz, 1H),7.38-7.28 (m, 2H), 7.14 (dd, J=8.5, 1.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H),1.80 (s, 3H), 1.60 (d, J=0.9 Hz, 6H).

Example 133-Chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (0.360 g, 0.943 mmol),8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate17] (0.392 g, 0.990 mmol), PdCl₂(dppf) DCM adduct (0.039 g, 0.047 mmol)and Cs₂CO₃ (0.615 g, 1.89 mmol) in dioxane (10 mL) and water (2.5 mL)was heated at 100° C. overnight. The cooled mixture was diluted withEtOAc and washed with water, dried and concentrated. The residue waspurified by column chromatography on silica gel, eluting withEtOAc-hexanes (gradient from 0-50%, then to 70% containing 1% MeOH), toprovide3-chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (0.361 g, 67% yield).Mass spectrum m/z 354 (M+H—H₂O)⁺, 394 (M+Na)⁺. ¹H NMR (500 MHz, MeOH-d₄)δ 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.81-7.69 (m, 1H),7.64-7.54 (m, 2H), 7.48 (dd, J=7.8, 1.1 Hz, 1H), 7.43-7.29 (m, 1H),7.31-7.24 (m, 1H), 7.18 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.07 (m, 1H), 6.92(dd, J=8.6, 5.3 Hz, 1H), 1.94-1.71 (m, 3H), 1.65-1.50 (m, 6H).

Example 143-Chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomer)

A sample of the mixture of four atropisomers of3-chloro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 13] (250 mg) was separated by chiral super-critical fluidchromatography as follows: column: CHIRALPAK® AD-H (5×25 cm, 5 μm);Mobile Phase: CO₂-IPA (60:40) at 220 mL/min, 35° C., 100 bar; samplepreparation: 21 mg/mL in MeOH; injection: 3.0 mL. The third peak elutingfrom the column provided3-chloro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer) as a white solid (24 mg). The chiral purity wasdetermined to be greater than 95%. Mass spectrum m/z 553 (M+H—H₂O)⁺,593(M+Na)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.09 (s, 1H), 7.95 (d, J=7.9 Hz,1H), 7.74 (d, J=1.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.43 (m, 1H), 7.37(d, J=7.5 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 7.11 (dd, J=8.6, 1.5 Hz, 1H),6.91 (d, J=8.6 Hz, 1H), 2.00-1.76 (m, 3H), 1.69-1.52 (m, 6H).

Examples 15 and 163-Cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomers)

Preparation 15A:3-Cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of 4 atropisomers)

A mixture of4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate23] (0.400 g, 1.08 mmol),8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 2] (0.573 g, 1.40 mmol), Cs₂CO₃ (0.700 g, 2.15 mmol), anddioxane (5 mL) was subjected to 3 evacuate-fill cycles with nitrogen.The mixture was treated with PdCl₂(dppf) DCM adduct (0.053 g, 0.064mmol) and subjected to 2 more evacuate-fill cycles with nitrogen. Themixture was heated at 88° C. for 2 days. The cooled mixture was dilutedwith EtOAc, washed sequentially with water and brine, and dried andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes (sequentially 50%, 75%, 85% and100%). The resulting impure product was purified by reverse-phasepreparative HPLC to give3-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (0.200 g, 32% yield).Mass spectrum m/z 576 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H),8.45 (s, 1H), 8.35 (br. s., 1H), 8.00-7.94 (m, 1H), 7.92 (s, 1H),7.77-7.68 (m, 2H), 7.60-7.52 (m, 2H), 7.41 (dd, J=6.6, 2.2 Hz, 1H),7.38-7.29 (m, 1H), 7.13 (t, J=10.1 Hz, 1H), 6.85 (t, J=8.1 Hz, 1H), 5.05(d, J=2.0 Hz, 1H), 3.74 (dd, J=8.1, 2.6 Hz, 3H), 1.73 (s, 3H), and1.48-1.43 (m, 6H).

Examples 15 and 16

A sample of3-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of 4 atropisomers) was separated by chiral super-critical fluidchromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm);Mobile Phase: CO₂-IPA (65:35) at 150 mL/min, 45° C. The second peakeluting from the column provided one single atropisomer of3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 15]. The chiral purity was determined to be greater than 94%.The fourth peak eluting from the column provided the other singleatropisomer of3-cyano-4-(S)-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 16]. The chiral purity was determined to be 99%. The massspectrum of each single atropisomer was the same as that of the mixtureof four atropisomers.

Example 173-Fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.080 g, 0.219 mmol),8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 2] (0.094 g, 0.230 mmol), PdCl₂(dppf) DCM adduct (9.0 mg,11.0 μmop and Cs₂CO₃ (0.143 g, 0.438 mmol) in dioxane (8.0 mL) and water(2.0 mL) was heated at 100° C. overnight. The cooled mixture was dilutedwith EtOAc and filtered. The filtrate was washed with water, dried andconcentrated. The residue was purified by reverse-phase preparativeHPLC, followed by purification by column chromatography on silica gel,eluting with EtOAc-hexanes (gradient from 50%-100%), to give3-fluoro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as an off-white solid (0.018 g, 15%yield). Mass spectrum m/z 551 (M+H—H₂O)⁺. ¹H NMR (500 MHz, MeOH-d₄) δ7.66 (d, J=10.4 Hz, 1H), 7.51 (s, 1H), 7.47-7.34 (m, 3H), 7.29 (t, J=7.2Hz, 2H), 7.22-7.11 (m, 1H), 7.09-6.97 (m, 1H), 6.90 (t, J=8.1 Hz, 1H),3.81-3.63 (m, 3H), 2.06 (br. s., 3H), and 1.77-1.58 (m, 6H).

Example 183-Fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.100 g, 0.274 mmol),8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] (0.146 g, 0.356 mmol), 2 M aqueous K₃PO₄ (0.41 mL,0.821 mmol), and THF (2.0 mL) was subjected to 3 evacuate-fill cycleswith nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (8.9mg, 0.014 mmol), and subjected to 2 more evacuate-fill cycles withnitrogen. The mixture was stirred at room temperature overnight. Themixture was diluted with EtOAc, washed sequentially with water andbrine, and dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially50%, 62%, 75% and 85%), to provide3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as an off-white solid (0.084 g, 53%yield). Mass spectrum m/z 551 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ11.39 (s, 1H), 8.21 (br. s., 1H), 7.99-7.92 (m, 3H), 7.84 (s, 1H), 7.73(ddt, J=14.4, 8.0, 1.4 Hz, 1H), 7.59 (br. s., 1H), 7.54-7.47 (m, 3H),7.40 (dd, J=7.2, 1.7 Hz, 1H), 7.34 (tt, J=7.9, 4.0 Hz, 1H), 7.04 (ddd,J=11.5, 8.6, 1.5 Hz, 1H), 6.88 (t, J=8.0 Hz, 1H), 4.99 (d, J=2.2 Hz,1H), 3.74 (dd, J=8.2, 1.0 Hz, 3H), 1.77 (s, 3H), and 1.49-1.42 (m, 6H).

Alternative Synthesis of3-Fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.050 g, 0.137 mmol),8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] (0.073 g, 0.178 mmol), Cs₂CO₃ (0.089 g, 0.274 mmol),and dioxane (0.8 mL) was subjected to 3 evacuate-fill cycles withnitrogen. The mixture was treated with PdCl₂(dppf) DCM adduct (6.7 mg,8.21 μmol), subjected to 2 more evacuate-fill cycles with nitrogen, andheated at 52° C. overnight. The cooled mixture was diluted with EtOAc,washed sequentially with water and brine, and dried and concentrated.The residue was purified by column chromatography on silica gel, elutingwith EtOAc-hexanes (sequentially 50%, 62% and 75%), to give3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as a white solid (0.034 g, 42% yield).

Example 193-Fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A sample of3-fluoro-4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) [Example 18] was separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AS-H(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (70:30) at 120 mL/min, 40° C.,100 bar; sample preparation: 3.6 mg/mL in MeOH; injection: 2.0 mL. Thefirst peak eluting from the column provided3-fluoro-4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.The chiral purity was determined to be greater than 99.4%. Mass spectrumm/z 551 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.39 (s, 1H), 8.21 (br.s., 1H), 8.00-7.92 (m, 2H), 7.84 (s, 1H), 7.73 (ddd, J=14.4, 8.0, 1.4Hz, 1H), 7.59 (br. s., 1H), 7.55-7.47 (m, 2H), 7.40 (dd, J=7.2, 1.4 Hz,1H), 7.33 (td, J=8.0, 4.0 Hz, 1H), 7.05 (dd, J=8.3, 1.4 Hz, 1H), 6.89(d, J=8.3 Hz, 1H), 4.99 (s, 1H), 3.74 (d, J=8.0 Hz, 3H), 3.17 (d, J=5.3Hz, 3H), 1.77 (s, 3H), and 1.46 (d, J=4.2 Hz, 6H).

Example 203-Fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of 4 atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.104 g, 0.285 mmol),8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate17] (0.147 g, 0.370 mmol), Cs₂CO₃ (0.186 g, 0.570 mmol), and dioxane(1.6 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Themixture was treated with PdCl₂(dppf) DCM adduct (14 mg, 0.017 mmol), andsubjected to two more evacuate-fill cycles with nitrogen. The mixturewas heated at 88° C. overnight. The cooled mixture was diluted withEtOAc, washed sequentially with water and brine, and dried andconcentrated. The residue was purified by reverse phase preparativeHPLC. The appropriate fractions were treated with saturated aqueousNaHCO₃ and concentrated to an aqueous residue which was extracted withEtOAc. The organic layer was washed with brine. The combined aqueouslayers were extracted with EtOAc, and the combined organic layers weredried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially50%, 65% and 75%), to provide3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (0.029 g, 18% yield).Mass spectrum m/z 537 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.81 (br.s., 1H), 11.39 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.7,2.1 Hz, 1H), 7.86-7.80 (m, 2H), 7.64 (t, J=9.2 Hz, 1H), 7.59 (br. s.,1H), 7.53-7.50 (m, 2H), 7.42-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.07-6.99(m, 1H), 6.97-6.88 (m, 1H), 4.98 (d, J=9.7 Hz, 1H), 1.81-1.75 (m, 3H),and 1.48-1.41 (m, 6H).

Examples 21 and 223-Fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide,and3-Fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Stropisomers)

A sample of3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of 4 atropisomers) [Example 20] was separated by chiralsuper-critical fluid chromatography as follows: column: CHIRALPAK® AD-H(3×25 cm, 5 μm); Mobile Phase: CO₂-IPA (75:25) at 180 mL/min, 40° C.,100 bar. The third peak eluting from the column provided3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 21]. The chiral purity was determined to be 98%. Mass spectrumm/z 537 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.83 (br. s., 1H),11.38 (s, 1H), 8.21 (br. s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.83 (d,J=1.1 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.47 (m,2H), 7.39 (dd, J=6.7, 1.9 Hz, 1H), 7.20 (br. s., 1H), 7.03-6.99 (m, 1H),6.99-6.94 (m, 1H), 4.97 (s, 1H), 1.77 (s, 3H), and 1.44 (d, J=5.3 Hz,6H).

The fourth peak eluting from the column provided3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 22]. The chiral purity was determined to be 95%. Mass spectrumm/z 537 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.80 (br. s., 1H),11.39 (s, 1H), 8.21 (br. s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.85-7.78 (m,2H), 7.59 (br. s., 2H), 7.54-7.46 (m, 2H), 7.38 (d, J=6.1 Hz, 1H), 7.19(br. s., 1H), 7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.99(s, 1H), 1.77 (s, 3H), and 1.46 (d, J=4.7 Hz, 6H).

Alternative Procedure for the Preparation of3-Fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 21]

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.118 g, 0.323 mmol),8-fluoro-3-(R)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 18] (0.166 g, 0.420 mmol), 2 M aqueous K₃PO₄ (0.485 mL,0.969 mmol) and THF (2.0 mL) was subjected to 3 evacuate-fill cycleswith nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (11 mg,0.016 mmol) and subjected to 2 more evacuate-fill cycles with nitrogen.The mixture was stirred at room temperature overnight, diluted withEtOAc, washed sequentially with water and brine, and dried andconcentrated. The residue was purified by column chromatography onsilica gel, eluting with EtOAc-hexanes (sequentially 50%, 62%, 75% and85%), to provide3-fluoro-4-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as an off-white solid (0.117 g, 65%yield). A sample of this material was separated by chiral super-criticalfluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5μm); Mobile Phase: CO₂-MeOH (70:30) at 180 mL/min, 45° C.; samplepreparation: 30 mg/mL; injection: 1.0 mL. The second peak eluting fromthe column provided3-fluoro-4-(R)-(3-(R)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.The chiral purity was determined to be greater than 99.9%. Mass spectrumm/z 537 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.83 (br. s., 1H),11.38 (s, 1H), 8.21 (br. s., 1H), 7.95 (d, J=10.8 Hz, 1H), 7.83 (d,J=1.1 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.47 (m,2H), 7.39 (dd, J=6.7, 1.9 Hz, 1H), 7.20 (br. s., 1H), 7.03-6.99 (m, 1H),6.99-6.94 (m, 1H), 4.97 (s, 1H), 1.77 (s, 3H), and 1.44 (d, J=5.3 Hz,6H).

Alternative Procedure for the Preparation of3-Fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 22]

Following the same procedure as that used for the alternativepreparation of Example 21,4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate 27] (0.118 g, 0.323 mmol) and8-fluoro-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate19] (0.166 g, 0.420 mmol) were converted to3-fluoro-4-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as an off-white solid (0.119 g, 66%yield). A sample of this material was separated by chiral super-criticalfluid chromatography as follows: column: CHIRALPAK® AS-H (3×25 cm, 5μm); Mobile Phase: CO₂-MeOH (75:25) at 180 mL/min, 45° C.; samplepreparation: 10 mg/mL; injection: 1.0 mL. The second peak eluting fromthe column provided3-fluoro-4-(R)-(3-(S)-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.The chiral purity was determined to be greater than 99.9%.

Example 233-Chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (135 mg, 0.354 mmol),1-(4-fluorophenyl)-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione[Intermediate 44] (164 mg, 0.389 mmol), andtetrakis(triphenylphosphine)palladium (20 mg, 0.018 mmol) in toluene(5.3 mL) and ethanol (1.8 mL) was bubbled with argon for several min.The mixture was treated with 2 M aqueous Na₂CO₃ (354 μl, 0.707 mmol),bubbled again with argon, and heated at 90° C. for 16 h. The cooledmixture was partitioned between EtOAc and water. The organic phase wasdried and concentrated. The residue was purified by columnchromatography on silica gel (24 g), eluting with EtOAc-hexanes(gradient from 25-100%), to give3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (103 mg, 49% yield).Mass spectrum m/z 579 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.52 (d,J=4.5 Hz, 1H), 8.29 (br. s., 1H), 8.13 (d, J=2.5 Hz, 1H), 7.91 (dd,J=7.9, 6.4 Hz, 1H), 7.85-7.80 (m, 1H), 7.64-7.54 (m, 3H), 7.53-7.45 (m,2H), 7.36 (dt, J=11.9, 8.7 Hz, 2H), 7.25 (ddd, J=7.3, 4.3, 1.2 Hz, 1H),7.03-6.83 (m, 1H), 6.73-6.47 (m, 1H), 5.97 (dd, J=7.9, 3.5 Hz, 1H),5.04-4.92 (m, 1H), 1.75 (d, J=1.5 Hz, 3H), 1.47-1.33 (m, 6H).

Example 243-Chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A sample of3-chloro-4-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) [Example 23] (103 mg) was separated bychiral super-critical fluid chromatography as follows: column:CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-IPA (60:40) at 85mL/min; sample preparation: 6.1 mg/mL in 1:1 MeCN-MeOH; injection: 1.0mL. The fourth peak eluting from the column was further purified bycolumn chromatography on silica gel (4 g), eluting with EtOAc-hexanes(gradient from 60-80%), to give a single atropisomer of3-chloro-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas an off-white solid (16 mg, 13% yield). Mass spectrum m/z 579(M+H—H₂O)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.06 (s, 1H), 7.78 (d, J=7.9 Hz,1H), 7.73 (d, J=1.1 Hz, 1H), 7.57-7.50 (m, 3H), 7.47-7.43 (m, 1H), 7.32(dd, J=7.5, 1.1 Hz, 1H), 7.27 (t, J=8.7 Hz, 2H), 7.11 (dd, J=8.5, 1.7Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.01 (d, J=7.9 Hz, 1H), 1.84 (s, 3H),1.58 (d, J=3.1 Hz, 6H).

Example 256-Chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(Mixture of Four Atropisomers)

A mixture of(S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate31] (100 mg, 0.259 mmol),8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate2] (112 mg, 0.272 mmol), Cs₂CO₃ (169 mg, 0.519 mmol) and PdCl₂(dppf) DCMadduct (16.9 mg, 0.021 mmol) in THF (4.3 mL) and water (1.1 mL) washeated at 50° C. for 17.5 h. The cooled mixture was diluted with EtOAc,washed sequentially with water and brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (24 g),eluting with EtOAc-hexanes (gradient from 50-80%). The impure productwas further purified by preparative HPLC to give6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of four atropisomers) (76 mg, 50% yield). Mass spectrum m/z 589(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.13 (br. s., 1H),7.94 (d, J=7.9 Hz, 1H), 7.76-7.68 (m, 2H), 7.46 (br. s., 1H), 7.40-7.28(m, 3H), 7.22-7.16 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.64 (m, 3H),2.95-2.82 (m, 1H), 2.40 (d, J=16.3 Hz, 1H), 1.94-1.70 (m, 3H), 1.70-1.61(m, 3H), 1.58-1.48 (m, 1H), 1.16-1.02 (m, 7H).

Example 266-Chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(single atropisomer)

A sample of6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of four atropisomers) [Example 25] (76 mg) was separated bychiral super-critical fluid chromatography as follows: column:CHIRALPAK® OD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (70:30) at 180mL/min, 35° C., 100 bar; sample preparation: 8.35 mg/mL in MeOH-DCM(4:1); injection: 3.0 mL. The first peak eluting from the column wasfurther purified by column chromatography on silica gel (4 g), elutingwith EtOAc-hexanes (gradient from 50-80%), to give6-chloro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamideas a white solid (33.6 mg, 47% yield). Mass spectrum m/z 589 (M+H)⁺. ¹HNMR (400 MHz, MeOH-d₄) δ 8.06-7.99 (m, 1H), 7.69 (s, 1H), 7.60 (ddd,J=14.3, 8.1, 1.4 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.34-7.27 (m, 2H),7.24 (dd, J=7.5, 1.1 Hz, 1H), 3.85 (d, J=7.9 Hz, 3H), 2.90 (dd, J=16.5,5.1 Hz, 1H), 2.56 (dd, J=16.4, 12.0 Hz, 1H), 2.10-2.02 (m, 1H),2.00-1.84 (m, 2H), 1.77 (s, 3H), 1.75-1.68 (m, 1H), 1.28 (d, J=3.1 Hz,1H), 1.22 (d, J=2.2 Hz, 6H).

Example 276-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(single atropisomer)

Preparation 27A:6-Fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of 2 atropisomers)

A mixture of(R)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(single enantiomer)[Intermediate 25] (5.00 g, 13.5 mmol),8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] (6.94 g, 16.9 mmol), 2 Maqueous K₃PO₄ (20.3 mL, 40.6 mmol) and THF (60 mL) was subjected tothree evacuate-fill cycles with nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino) ferrocene palladium(II) chloride (441mg, 677 μmol) and subjected to two more evacuate-fill cycles withnitrogen. The mixture was stirred at room temperature overnight. Themixture was diluted with EtOAc, washed sequentially with water andbrine, and dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially50%, 62%, 75% and 85%), to give6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of two atropisomers) as an off-white solid (6.77 g, 87% yield).Mass spectrum m/z 573 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79-10.74(m, 1H), 8.05 (br. s., 1H), 7.98-7.93 (m, 1H), 7.76-7.69 (m, 1H),7.57-7.51 (m, 1H), 7.43 (br. s., 1H), 7.40-7.26 (m, 4H), 4.19-4.13 (m,1H), 3.74-3.68 (m, 3H), 2.94-2.84 (m, 1H), 2.49-2.35 (m, 2H), 1.92-1.80(m, 3H), 1.76-1.68 (m, 3H), 1.62-1.52 (m, 1H), and 1.12-1.06 (m, 6H).

Example 27

A sample of6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of two atropisomers) was separated by chiral super-criticalfluid chromatography as follows: column: CHIRALPAK® AS-H (3×25 cm, 5μm); Mobile Phase: CO₂-MeOH (70:30) at 120 mL/min, 35° C., 100 bar;sample preparation: 9 mg/mL in MeOH; injection: 1.7 mL. The first peakeluting from the column provided6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide.The chiral purity was determined to be greater than 99.5%. Mass spectrumm/z 573 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.05 (br. s.,1H), 7.96 (d, J=7.8 Hz, 1H), 7.72 (ddd, J=14.3, 8.0, 1.2 Hz, 1H), 7.55(d, J=10.8 Hz, 1H), 7.44 (br. s., 1H), 7.40-7.36 (m, 1H), 7.35-7.28 (m,3H), 4.18 (s, 1H), 3.72 (d, J=8.0 Hz, 3H), 2.89 (dd, J=16.9, 4.4 Hz,1H), 2.45-2.37 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.82 (m, 2H), 1.57 (td,J=11.7, 3.6 Hz, 1H), and 1.15-1.11 (m, 1H).

Example 286-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(single atropisomer)

Following the procedure used to prepare Example 27,(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(single enantiomer) [Intermediate 26] (0.045 g, 0.122 mmol) and8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] (0.065 g, 0.158 mmol) were converted into6-fluoro-5-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide(mixture of two atropisomers) as a yellow solid (0.035 g, 49% yield).Separation of a sample of this material by chiral super-critical fluidchromatography, using the conditions used to separate Example 27,provided (as the first peak to elute from the column)6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide.The chiral purity was determined to be greater than 99.5%. The relativeand absolute configurations were determined by x-ray crystallography.Mass spectrum m/z 573 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.77 (s, 1H),8.05 (br. s., 1H), 7.94 (dd, J=7.9, 1.2 Hz, 1H), 7.56-7.52 (m, 1H), 7.43(br. s., 1H), 7.40-7.36 (m, 1H), 7.35-7.30 (m, 2H), 7.28 (dd, J=7.5, 1.4Hz, 1H), 4.15 (s, 1H), 3.75-3.70 (m, 3H), 2.90 (dd, J=16.8, 4.6 Hz, 1H),2.47-2.39 (m, 1H), 1.93-1.82 (m, 3H), 1.74 (s, 3H), 1.57 (td, J=11.7,4.2 Hz, 1H), 1.16-1.11 (m, 1H), and 1.10 (d, J=1.9 Hz, 6H). [α]D: +63.8°(c 2.1, CHCl₃). DSC melting point onset temperature=202.9° C. (heatingrate=10° C./min.).

The absolute configuration of Example 28 was confirmed by single crystalx-ray analysis of crystals prepared by dissolving the compound in excessmethanol and slowly evaporating the solvent at room temperature toprovide a di-methanol solvate (crystalline form M2-1). Unit celldimensions: a=9.24 Å, b=7.97 Å, c=22.12 Å, α=90.0°, β=94.1°, γ=90.0°;Space group: P2₁; Molecules of Example 28/asymmetric unit: 1;Volume/Number of molecules in the unit cell=813 Å³; Density(calculated)=1.301 g/cm³. Fractional atomic coordinates at 173 K aregiven in Table 6, and a depiction of the structure is given in FIG. 5.

Alternative Synthesis of Example 28

A mixture of(S)-5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide[Intermediate11] (5.00 g, 13.54 mmol),8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate10] (6.67 g, 16.25 mmol), tripotassium phosphate (2 M in water) (20.31mL, 40.6 mmol), and tetrahydrofuran (25 mL) was subjected to 3evacuate-fill cycles with nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.441 g,0.677 mmol) and the mixture was subjected to 2 more evacuate-fill cycleswith nitrogen. The mixture was stirred at room temperature overnight,then was diluted with EtOAc, washed sequentially with water and brine,and dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially50%, 62%, 75% and 85%), to provide6-fluoro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3-(S)-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamideas a white solid (6.58 g, 85% yield).

Material prepared by this method (40.03 g, 69.9 mmol) was separated bychiral super-critical fluid chromatography to give (2S,5R)-6-fluoro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide.Further purification was achieved by suspending this material inmethanol, sonicating for 5 min, collection of the solid by filtration,rinsing the collected solid with methanol and drying at room temperatureunder reduced pressure to give a white solid (22.0 g, 90% yield).

Example 294-(R)-(3-(S)-(8-Fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide[Intermediate28] (0.091 g, 0.252 mmol),8-fluoro-1-methyl-3-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione[Intermediate 10] (0.134 g, 0.327 mmol), 2 M aqueous K₃PO₄ (0.378 mL,0.756 mmol), and THF (2.0 mL) was subjected to three evacuate-fillcycles with nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (8.2mg, 0.013 mmol) and subjected to two additional evacuate-fill cycleswith nitrogen. The mixture was stirred at room temperature overnight,then was diluted with EtOAc, washed sequentially with water and brine,and dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes (sequentially50%, 62%, 75% and 85%) to give4-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide(mixture of two atropisomers) as pale yellow solid (0.087 g, 59% yield).Mass spectrum m/z 547 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.20 (s,1H), 8.10 (br. s., 1H), 7.97 (ddd, J=7.9, 7.2, 1.0 Hz, 1H), 7.90 (s,1H), 7.78 (s, 1H), 7.76-7.68 (m, 1H), 7.53-7.48 (m, 1H), 7.44 (dd,J=7.9, 1.2 Hz, 1H), 7.40 (br. s., 1H), 7.36-7.30 (m, 1H), 7.23 (dd,J=7.4, 1.2 Hz, 1H), 6.98 (ddd, J=12.0, 8.4, 1.5 Hz, 1H), 6.68 (t, J=7.9Hz, 1H), 4.94 (d, J=3.1 Hz, 1H), 3.73 (dd, J=8.2, 3.5 Hz, 3H), 2.17 (s,3H), 1.66 (s, 3H), and 1.48-1.41 (m, 6H).

A sample of this material was separated by chiral super-critical fluidchromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm);Mobile Phase: CO₂-MeOH (65:35) at 150 mL/min, 40° C.; samplepreparation: 15 mg/mL in MeOH; injection: 1.5 mL. The second peakeluting from the column provided4-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazole-1-carboxamide.The chiral purity was determined to be greater than 99%. Mass spectrumm/z 547 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.10 (br.s., 1H), 7.97 (dd, J=7.9, 1.0 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J=1.1 Hz,1H), 7.72 (ddd, J=14.3, 8.0, 1.5 Hz, 1H), 7.53-7.48 (m, 1H), 7.44 (dd,J=7.8, 1.1 Hz, 1H), 7.40 (br. s., 1H), 7.33 (td, J=8.0, 4.2 Hz, 1H),7.23 (dd, J=7.5, 1.1 Hz, 1H), 6.99 (dd, J=8.5, 1.5 Hz, 1H), 6.69 (d,J=8.6 Hz, 1H), 4.94 (s, 1H), 2.20-2.14 (m, 3H), 1.66 (s, 3H), and 1.45(d, J=3.6 Hz, 6H).

Examples 30 and 314-(R)-(3-(5-Chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomers)

Preparation 30A:4-(3-(5-Chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.098 g, 0.268 mmol),5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 33] (0.144 g, 0.349 mmol), Cs₂CO₃ (0.175 g, 0.537 mmol),and dioxane (1.6 mL) was subjected to three evacuate-fill cycles withnitrogen. The mixture was treated with PdCl₂(dppf) DCM adduct (0.013 g,0.016 mmol) and subjected to two more evacuate-fill cycles withnitrogen. The mixture was heated at 52° C. overnight. The cooled mixturewas diluted with EtOAc, washed sequentially with water and brine, anddried and concentrated. The residue was purified by reverse-phasepreparative HPLC. The appropriate fractions were treated with saturatedaqueous NaHCO₃ and concentrated. The residue was partitioned betweenEtOAc and water, and the organic layer was washed with brine. Theaqueous layers were extracted with EtOAc, and the combined organiclayers were dried and concentrated. The residue was purified twice bycolumn chromatography on silica gel, eluting with EtOAc-hexanes(sequentially 50%, 65% and 75%) to give4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a yellow solid (0.013 g, 8% yield).Mass spectrum m/z 571, 573 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 11.39 (d,J=5.3 Hz, 1H), 8.30-8.24 (m, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.5,1.7 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.55-7.47 (m, 2H),7.42-7.39 (m, 1H), 7.04-6.99 (m, 1H), 6.93 (d, J=8.6 Hz, 0.6H), 6.84 (d,J=8.6 Hz, 0.4H), 6.57 (td, J=7.3, 3.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H),4.98 (s, 1H), 1.78 (d, J=1.9 Hz, 3H), and 1.45 (d, J=3.9 Hz, 6H).

Examples 30 and 31

A sample of4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of 4 atropisomers) was separated by chiral super-critical fluidchromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm);Mobile Phase: CO₂-IPA (55:45) at 120 mL/min, 45° C., 100 bar; samplepreparation: 5.6 mg/mL in MeOH; injection: 1.7 mL. The second peakeluting from the column provided one single atropisomer of4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 30]. The chiral purity was determined to be greater than 97.5%.Mass spectrum m/z 571 (M+H)⁺. The fourth peak eluting from the columnprovided the other single atropisomer of4-(R)-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 31]. The chiral purity was determined to be greater than 99.5%.Mass spectrum m/z 553 (M+H—H₂O)⁺.

Examples 32 and 333-Chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(32), and3-Chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(33) (Single Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (1.11 g, 2.91 mmol),5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 33] (1.00 g, 2.42 mmol) and Cs₂CO₃ (1.58 g, 4.85 mmol) inTHF (8 mL) and water (2 mL) was bubbled with argon for three min. Themixture was treated with PdCl₂(dppf) DCM adduct (0.099 g, 0.121 mmol)and heated at 60° C. overnight. The cooled mixture was diluted withEtOAc and washed sequentially with water and brine. The combined aqueouslayers were extracted with DCM containing a small amount of MeOH. Thecombined organic layers were dried and concentrated until a tanprecipitate formed, which was removed by filtration. The filtrate wasconcentrated and purified by column chromatography on silica gel (120g), eluting with EtOAc-DCM (sequentially 70%, 80%, and 100%), to give3-chloro-4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a yellow solid (993 mg, 69% yield).The material was separated by chiral super-critical fluid chromatographyas follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase:CO₂-IPA (50:50) at 150 mL/min, 45° C., 100 bar; sample preparation: 5.6mg/mL in MeOH-DCM (1:1); injection: 3 mL. The second peak eluting fromthe column provided3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 32]. Mass spectrum m/z 587 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.50 (s, 1H), 8.27 (s, 2H), 8.14 (s, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.59(d, J=6.8 Hz, 1H), 7.56-7.46 (m, 2H), 7.29 (dd, J=7.4, 1.2 Hz, 1H), 7.01(dd, J=8.4, 1.5 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.55 (t, J=7.3 Hz, 1H),5.98 (s, 1H), 5.75 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.46-1.42 (m,6H).

The fourth peak eluting from the column provided3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 33]. Mass spectrum m/z 569 (M+H—H₂O)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.49 (s, 1H), 8.34-8.24 (m, 2H), 8.14 (s, 1H), 7.84 (d,J=1.1 Hz, 1H), 7.60 (d, J=6.6 Hz, 1H), 7.56-7.46 (m, 2H), 7.28 (dd,J=7.4, 1.4 Hz, 1H), 6.99 (dd, J=8.5, 1.7 Hz, 1H), 6.72 (d, J=8.4 Hz,1H), 6.57 (t, J=7.3 Hz, 1H), 5.99 (s, 1H), 5.75 (s, 1H), 4.98 (s, 1H),1.71 (s, 3H), 1.45-1.42 (m, 6H). [α]D: +332.34° (c 2.0, CHCl₃).

Alternative Preparation of Example 33

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (50.5 g, 132 mmol),5-chloro-2-(S)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 35] (60.1 g, 146 mmol) and Cs₂CO₃ (86 g, 265 mmol) in THF(342 mL) and water (85 mL) was bubbled with nitrogen for 5 min, then wastreated with PdCl₂(dppf) DCM adduct (11.9 g, 14.57 mmol). Bubbling withnitrogen was continued for 5 min more, then the mixture was heated at62° C. under nitrogen for 20 h. The mixture was cooled to roomtemperature, MeOH (300 mL) was added with stirring followed 15 min laterby the addition of water (2 L) to give a rusty brown colored gum. Thesupernatant was removed, the gummy residue was washed twice with waterand then suspended in EtOAc (2 L) with stirring for one h. The mixturewas filtered, the filtrate was concentrated to about 1-1.5 L and treatedwith heptane (3 L). The mixture was stirred for two days, theprecipitate was collected by filtration, washed with heptane and driedunder vacuum to give a yellow solid (104 g). The solid was dissolved inTHF, absorbed on CELITE®, dried under vacuum, placed on a silica gelplug and eluted with heptane/EtOAc (10:90) to give an orange-yellow oil(74.87 g). The material was subjected to column chromatography on silicagel (3 kg), eluting with EtOAc-hexanes (gradient from 40-90%), to give3-chloro-4-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as a yellow foam (44 g, 51% yield). Toremove residual palladium, the residue was dissolved in EtOAc (about 300mL) and stirred with a 10% aqueous solution of N-acetyl-L-cysteine (500mL) overnight. The organic layer was treated again with a 10% solutionof N-acetyl-L-cysteine (500 mL) for six h, then was washed sequentiallywith 5% NH₄OH (twice) and brine, dried and concentrated to a yellow foam(43 g). The material was separated by chiral super-critical fluidchromatography as follows: column: CHIRALPAK® AS-H (2×50 cm, 10 μm);Mobile Phase: CO₂-MeOH (55:45) at 140 mL/min, 40° C., 100 bar; samplepreparation: 56 mg/mL in MeOH-DCM (1:1); injection: 3.33 mL. The firstpeak eluting from the column provided3-chloro-4-(R)-(3-(S)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 33] as a yellow solid (18.3 g, 24% yield).

The absolute configuration of Example 33 was confirmed by single crystalx-ray analysis of crystals prepared by dissolving the compound in excessmethanol and slowly evaporating the solvent at room temperature toprovide a di-methanol solvate (crystalline form M2-1). Unit celldimensions: a=7.41 Å, b=9.74 Å, c=44.55 Å, α=90.0°, β=90.0°, γ=90.0°;Space group: P2₁2₁2₁; Molecules of Example 33/asymmetric unit: 1;Volume/Number of molecules in the unit cell=3214 Å³; Density(calculated)=1.346 g/cm³. Fractional atomic coordinates at 173 K aregiven in Table 7, and a depiction of the structure is given in FIG. 6.

Example 343-Chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (0.076 g, 0.200 mmol),5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 37] (0.072 g, 0.182 mmol) and Cs₂CO₃ (0.118 g, 0.363 mmol)in THF (3 mL) and water (0.75 mL) was bubbled with nitrogen for 2 min,then was treated with PdCl₂(dppf) DCM adduct (7.4 mg, 9.09 μmol).Bubbling with nitrogen was continued for 30 sec and the reaction vesselwas sealed. The mixture was stirred at room temperature overnight, thenwas diluted with EtOAc and washed sequentially with water and brine. Thecombined aqueous layers were extracted with DCM. The combined organiclayers were dried and concentrated. The residue was purified by columnchromatography on silica gel, eluting with EtOAc-hexanes, to give3-chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a yellow solid (0.049 g, 43% yield).Mass spectrum m/z 571 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.52-11.48(m, 1H), 8.27 (br. s., 1H), 8.15-8.09 (m, 2H), 7.84 (s, 1H), 7.59 (br.s., 1H), 7.56-7.46 (m, 2H), 7.30-7.26 (m, 1H), 7.03-6.97 (m, 1H), 6.72(d, J=8.4 Hz, 1H), 6.60-6.51 (m, 2H), 5.85 (s, 1H), 4.98 (s, 1H), 1.71(s, 3H), 1.46-1.42 (m, 6H).

Examples 35 and 363-Chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomers)

A sample of3-chloro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) [Example 34] (690 mg) was separated bychiral super-critical fluid chromatography as follows: column:CHIRALPAK® IB (2×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (63:37) at 50mL/min, 45° C., 100 bar. The first peak eluting from the column providedone single atropisomer of3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 35]. Mass spectrum m/z 571 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.50 (s, 1H), 8.27 (br. s., 1H), 8.14 (s, 1H), 8.11 (d, J=7.5 Hz, 1H),7.84 (d, J=1.1 Hz, 1H), 7.59 (br. s., 1H), 7.56-7.51 (m, 1H), 7.49-7.46(m, 1H), 7.29 (dd, J=7.5, 1.3 Hz, 1H), 7.23 (dd, J=10.3, 7.5 Hz, 1H),7.01 (dd, J=8.4, 1.5 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.54 (td, J=7.4,5.2 Hz, 1H), 5.85 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.48-1.41 (m,6H).

The third peak eluting from the column provided the other singleatropisomer of3-chloro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 36]. Mass spectrum m/z 553 (M+H—H₂O)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.49 (s, 1H), 8.27 (br. s., 1H), 8.14 (s, 1H), 8.10 (d,J=7.7 Hz, 1H), 7.83 (s, 1H), 7.59 (br. s., 1H), 7.56-7.45 (m, 2H),7.30-7.20 (m, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.56(td, J=7.5, 5.3 Hz, 1H), 5.85 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H),1.45-1.42 (m, 6H).

Example 373-Chloro-7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (0.051 g, 0.135 mmol),5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 32] (0.050 g, 0.122 mmol) and Cs₂CO₃ (0.080 g, 0.245 mmol)in THF (2 mL) and water (0.5 mL) was bubbled with nitrogen for 2 min,then was treated with PdCl₂(dppf) DCM adduct (5.0 mg, 6.12 μmol).Bubbling with nitrogen was continued for 30 sec and the reaction vesselwas sealed. The mixture was heated at 60° C. overnight. The cooledmixture was diluted with DCM and MeOH, dried and concentrated. Theresidue was purified by column chromatography on silica gel, elutingwith EtOAc-hexanes, to give3-chloro-7-(2-hydroxypropan-2-yl)-4-(3-(5-methoxy-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a yellow solid (32.8 mg, 44% yield).Mass spectrum m/z 583 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.51-11.47(m, 1H), 8.27 (br. s., 1H), 8.14 (d, J=1.5 Hz, 1H), 7.93 (d, J=7.5 Hz,1H), 7.83 (s, 1H), 7.59 (br. s., 1H), 7.55-7.45 (m, 3H), 7.30-7.25 (m,1H), 7.03-6.97 (m, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.56 (q, J=7.6 Hz, 1H),5.90 (s, 1H), 4.98 (s, 1H), 3.91 (s, 3H), 1.69 (s, 3H), 1.45-1.42 (m,6H).

Examples 38 and 393-Chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (0.139 g, 0.364 mmol),6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione[Intermediate 36] (0.127 g, 0.331 mmol) and Cs₂CO₃ (0.215 g, 0.661 mmol)in THF (3.0 mL) and water (0.75 mL) was bubbled with argon for 3 min,then was treated with PdCl₂(dppf) DCM adduct (0.013 g, 0.017 mmol). Themixture was bubbled with argon for 30 sec more and the reaction vesselwas sealed. The mixture was stirred at 50° C. for 5 h. The cooledmixture was diluted with EtOAc and washed sequentially with water andbrine. The combined aqueous layers was extracted with EtOAc, and thecombined organic layers were dried and concentrated. The residue waspurified by column chromatography on silica gel (80 g), eluting withEtOAc-hexanes (90%, then 100%), to give3-chloro-4-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a tan solid (62.7 mg, 32% yield). Thismaterial was separated by chiral super-critical fluid chromatography asfollows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH(60:40) at 85 mL/min; sample preparation: 9 mg/mL in MeOH-DMSO;injection: 2 mL. The third peak eluted from the column provided onesingle atropisomer of3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 38]. Mass spectrum m/z 559 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.50 (s, 1H), 8.27 (br. s., 1H), 8.14 (s, 1H), 7.83 (d, J=0.9 Hz, 1H),7.69 (dd, J=4.6, 0.7 Hz, 1H), 7.59 (br. s., 1H), 7.54-7.49 (m, 1H),7.47-7.43 (m, 1H), 7.26 (dd, J=7.4, 1.2 Hz, 1H), 7.03 (d, J=4.6 Hz, 1H),6.99 (dd, J=8.6, 1.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.98(s, 1H), 1.70 (s, 3H), 1.45-1.42 (m, 6H).

The fourth peak eluted from the column provided the other singleatropisomer of3-chloro-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 39]. Mass spectrum m/z 541 (M+H—H₂O)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.49 (s, 1H), 8.27 (br. s., 1H), 8.13 (s, 1H), 7.83 (d,J=0.9 Hz, 1H), 7.73-7.65 (m, 2H), 7.59 (br. s., 1H), 7.54-7.43 (m, 2H),7.26 (dd, J=7.5, 1.3 Hz, 1H), 7.05 (d, J=4.6 Hz, 1H), 6.98 (dd, J=8.5,1.7 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.28 (s, 1H), 1.70 (s, 3H), 1.43(d, J=2.9 Hz, 6H).

Examples 40 and 413-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Single Atropisomers)

Preparation 40A:3-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (0.200 g, 0.548 mmol),5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione[Intermediate 37] (0.260 g, 0.657 mmol) and Cs₂CO₃ (0.357 g, 1.10 mmol)in dioxane (4 mL) and water (1 mL) was bubbled with nitrogen for 2 min,then was treated with PdCl₂(dppf) DCM adduct (0.022 g, 0.027 mmol).Bubbling with nitrogen was continued for 30 sec and the reaction vesselwas sealed. The mixture was heated at 60° C. overnight. The cooledmixture was diluted with EtOAc and washed sequentially with water andbrine. The combined aqueous layers were extracted with DCM, and combinedorganic layers were dried and concentrated. The residue was purified bycolumn chromatography on silica gel, eluting with EtOAc-hexanes, to give3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a yellow solid (0.194 g, 63% yield).

Examples 40 and 41

A sample of3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) was separated by chiral super-criticalfluid chromatography as follows: column: CHIRALPAK® OD-H (5×25 cm, 5μm); Mobile Phase: CO₂-IPA (55:45) at 120 mL/min, 50° C., 100 bar;sample preparation: 6.8 mg/mL in MeOH—CHCl₃ (1:1); injection: 1 mL. Thefirst peak eluting from the column provided one single atropisomer of3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 40]. Mass spectrum m/z 555 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.40 (s, 1H), 8.21 (br. s., 1H), 8.12 (d, J=7.5 Hz, 1H), 7.95 (d,J=10.8 Hz, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.60 (br. s., 1H), 7.56-7.46 (m,2H), 7.41 (dd, J=7.4, 1.4 Hz, 1H), 7.23 (dd, J=10.2, 7.4 Hz, 1H), 7.02(dd, J=8.6, 1.5 Hz, 1H), 6.88-6.82 (m, 1H), 6.56 (td, J=7.4, 5.2 Hz,1H), 5.86 (s, 1H), 4.98 (s, 1H), 1.77 (s, 3H), 1.47-1.42 (m, 6H).

The third peak eluting from the column provided the other singleatropisomer of3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 41]. Mass spectrum m/z 537 (M+H—H₂O)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.41 (s, 1H), 8.29-8.17 (m, 1H), 8.13 (d, J=7.3 Hz, 1H),7.96 (d, J=10.8 Hz, 1H), 7.85 (d, J=1.1 Hz, 1H), 7.65-7.57 (m, 1H),7.57-7.47 (m, 2H), 7.43 (d, J=1.5 Hz, 1H), 7.28-7.21 (m, 1H), 7.02 (d,J=1.5 Hz, 1H), 6.90-6.83 (m, 1H), 6.64-6.53 (m, 1H), 5.87 (s, 1H), 4.99(s, 1H), 1.78 (s, 3H), 1.48-1.44 (m, 6H).

Alternative Preparation of3-Fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer) [Example 41]

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (6.00 g, 16.4 mmol),5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(single enantiomer)[Intermediate 38] (7.81 g, 19.7 mmol), 2 M aqueousK₃PO₄ (24.6 mL, 49.3 mmol), and THF (70 mL) was subjected to threeevacuate-fill cycles with nitrogen. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (0.535g, 0.821 mmol), and subjected to two more evacuate-fill cycles withnitrogen. The mixture was stirred at room temperature overnight. Themixture was diluted with EtOAc, washed sequentially with water andbrine, and dried. The aqueous layer was filtered and the collected solidwas added to the organic layer. The organic layer was concentrated, andthe residue was purified by column chromatography on silica gel, elutingwith EtOAc-hexanes (sequentially 50%, 62%, 75%, 85% and 100%), toprovide 3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of two atropisomers) as a yellow solid (8.55 g, 94% yield). Asample of this material (combined with other batches of the samematerial) was separated by chiral super-critical fluid chromatography asfollows: column: CHIRALPAK® IC (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH(50:50) at 165 mL/min, 45° C., 100 bar; sample preparation: 55 mg/mL inMeOH-THF-DMSO (2:1:1); injection: 3 mL. The first peak eluting from thecolumn provided a single atropisomer of3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Example 41].

Example 423-Chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (36 mg, 0.094 mmol),(Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one[Intermediate 40] (42.8 mg, 0.104 mmol), EtOH (1mL), toluene (1 mL) and 2 M aqueous Na₂CO₃ (0.16 mL, 0.311 mmol) wasbubbled with nitrogen for 5 min. The mixture was treated withtetrakis(triphenylphosphine)palladium (8.7 mg, 7.55 μmol), and thereaction vessel was sealed and heated at 90° C. for 16 h. The cooledmixture was partitioned between EtOAc and water, and the organic phasewas dried and concentrated. The residue was purified by columnchromatography on silica gel (4 g), eluting with MeOH-DCM containing 1%TEA (gradient from 0-5%). The resulting material was further purifiedusing preparative HPLC (PHENOMENEX® Axia Cis 30×100 mm), eluting withMeCN-water containing 0.1% TFA (gradient from 20-100%, 30 mL/min). Theappropriate fractions were treated with saturated aqueous NaHCO₃ andconcentrated. The residue was partitioned between EtOAc and water, andthe organic phase was washed with brine, dried and concentrated to give3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (2.5 mg, 4% yield). Massspectrum m/z 569 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.38-8.23(m, 1H), 7.73 (d, J=1.5 Hz, 2H), 7.70-7.66 (m, 1H), 7.64 (s, 1H),7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.20 (m,1H), 7.10-6.78 (m, 1H), 3.70 (s, 2H), 3.67 (s, 1H), 1.65 (s, 4H), 1.64(s, 2H).

Example 433-Chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (singleatropisomer)

A sample of3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) [Example 42] (110 mg) was separated bychiral super-critical fluid chromatography as follows: column: Lux Cel-4(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (60:40) at 85 mL/min; samplepreparation: 6.7 mg/mL in MeOH-acetone (9:1); injection: 3.0 mL. Thefourth peak eluting from the column provided a single atropisomer of3-chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a yellow solid (20 mg, 18% yield). Mass spectrum m/z 569 (M+H—H₂O)⁺.¹H NMR (400 MHz, chloroform-d) δ 10.44 (s, 1H), 8.41-8.17 (m, 1H),7.78-7.72 (m, 2H), 7.68 (s, 1H), 7.65-7.60 (m, 1H), 7.59-7.54 (m, 1H),7.46 (d, J=7.5 Hz, 1H), 7.34-7.28 (m, 2H), 7.25 (s, 1H), 7.01 (d, J=8.6Hz, 1H), 3.70 (s, 3H), 1.64 (s, 6H).

Example 443-Chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Mixture ofFour Atropisomers)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (30 mg, 0.079 mmol),3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione[Intermediate 41] (40.6 mg, 0.094 mmol), EtOH (1 mL), toluene (1 mL) and2 M aqueous Na₂CO₃ (0.13 mL, 0.26 mmol) was bubbled with nitrogen for 5min. The mixture was treated with tetrakis(triphenylphosphine)palladium(7.3 mg, 6.29 μmol), and the reaction vessel was sealed and heated at90° C. for 16 h. The cooled mixture was partitioned between EtOAc andwater, and the organic phase was dried and concentrated. The residue waspurified by column chromatography on silica gel (12 g), eluting withMeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting materialwas further purified using preparative HPLC (PHENOMENEX® Axia Cis 30×100mm), eluting with MeCN-water containing 0.1% TFA (gradient from 20-100%,10 min, 30 mL/min). The appropriate fractions were treated withsaturated aqueous NaHCO₃ and concentrated. The residue was partitionedbetween EtOAc and water, and the organic phase was washed with brine,dried and concentrated to provide3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (6 mg, 11% yield). Massspectrum m/z 587 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) □δ 10.46 (s,1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H),7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd,J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). ¹⁹F NMR (400 MHz, chloroform-d) δ−121.34.

Example 453-Chloro-4-(R)-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A sample of3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) [Example 44] (100 mg) was separated bychiral super-critical fluid chromatography as follows: column: Lux Cel-4(3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH (60:40) at 85 mL/min, 50° C.,100 bar; sample preparation: 6.7 mg/mL in MeOH-acetone (1:1); injection:3.0 mL. The fourth peak eluting from the column provided a singleatropisomer of3-chloro-4-(R)-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideas a yellow solid (9.3 mg). Mass spectrum m/z 569 (M+H—H₂O)⁺. ¹H NMR(400 MHz, chloroform-d) δ 10.45 (s, 1H), 8.11 (d, J=7.3 Hz, 1H), 7.73(s, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.67-7.61 (m,1H), 7.56 (dd, J=7.9, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.51-7.42 (m, 2H),7.26-7.19 (m, 2H), 7.00 (d, J=8.6 Hz, 1H), 3.90 (d, J=8.1 Hz, 3H), 1.64(s, 6H). ¹⁹F NMR (376 MHz, chloroform-d) δ −121.33.

Example 464-(2-Chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(Mixture of Four Atropisomers)

A mixture of4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate27] (40 mg, 0.110 mmol),3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione[Intermediate 41] (47 mg, 0.110 mmol), Cs₂CO₃ (107 mg, 0.329 mmol),dioxane (8 mL) and water (2 mL) was bubbled with nitrogen for 10 min.The mixture was treated with PdCl₂(dppf) DCM adduct (7.2 mg, 8.76 μmol),and heated at 60° C. overnight. The cooled mixture was partitionedbetween EtOAc and water. The organic phase was dried and concentrated.The residue was purified by column chromatography on silica gel, elutingwith MeOH-DCM (gradient from 0-5%), to give4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) as a white solid (20 mg, 31% yield). Massspectrum m/z 569 (M+H—H₂O)⁺. ¹H NMR (400 MHz, chloroform-d) δ 10.46 (s,1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H),7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd,J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). ¹⁹F NMR (400 MHz, chloroform-d) δ−121.34, −127.34.

Example 473-Chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(single atropisomer)

A mixture of4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide[Intermediate3] (103 mg, 0.269 mmol),3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione[Intermediate42] (140 mg, 0.336 mmol), THF (5 mL), 2 M aqueous K₃PO₄ (0.504 mL, 1.01mmol) was bubbled with nitrogen for 15 min. The mixture was treated with1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (17.5mg, 0.027 mmol) and was stirred at room temperature overnight. Themixture was concentrated, and the residue was partitioned between EtOAcand water. The organic phase was dried and concentrated. The residue waspurified by preparative HPLC. The appropriate fractions were treatedwith saturated aqueous NaHCO₃ and concentrated. The aqueous residue wasextracted with EtOAc. The organic phase was washed sequentially withwater and brine, and dried and concentrated to give3-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide(mixture of four atropisomers) (30 mg, 15% yield). This material wasseparated by chiral super-critical fluid chromatography as follows:column: CHIRALCEL® OJ-H (3×25 cm, 5 μm); Mobile Phase: CO₂-MeOH-MeCN(65:17.5:17.5) at 85 mL/min; sample preparation: 6.8 mg/mL in MeOH—CHCl₃(1:1); injection: 3.0 mL. The first peak eluting from the columnprovided a single atropisomer of3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide.Mass spectrum m/z 573 (M+H—H₂O)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ11.63-11.48 (m, 1H), 8.39-8.25 (m, 1H), 8.17-8.12 (m, 1H), 7.99-7.92 (m,1H), 7.88-7.85 (m, 1H), 7.85-7.81 (m, 1H), 7.81-7.76 (m, 1H), 7.76-7.70(m, 1H), 7.70-7.62 (m, 2H), 7.57-7.46 (m, 1H), 7.32-7.20 (m, 1H),7.13-6.99 (m, 1H), 6.77-6.63 (m, 1H), 5.10-4.98 (m, 1H), 1.47-1.45 (m,6H). ¹⁹F NMR (400 MHz, chloroform-d) δ −129.63.

The compounds in Table 10 were prepared by procedures analogous to thosedescribed above, using Intermediates described or prepared by methodssimilar to those described.

TABLE 10 Formula Mass Ex. Structure Description weight spectrum 48

Single atropisomer Peak 4 589.00 571 (M + H − H₂O)⁺ 49

Mixture of four atropisomers 572.54 555 (M + H − H₂O)⁺ 50

Single atropisomer Peak 2 572.54 555 (M + H − H₂O)⁺ 51

Single atropisomer Peak 3 554.55 537 (M + H − H₂O)⁺ 52

Single atropisomer Peak 2 571.60 554 (M + H − H₂O)⁺ 53

Single atropisomer Peak 3 571.01 553 (M + H − H₂O)⁺ 54

Single atropisomer Peak 4 571.01 553 (M + H − H₂O)⁺ 55

Single atropisomer Peak 2 575.04 575 (M + H)⁺ 56

Single atropisomer Peak 4 575.04 575 (M + H)⁺ 57

Single atropisomer Peak 1 593.03 593 (M + H)⁺ 58

Single atropisomer Peak 2 592.08 592 (M + H)⁺ 59

Single atropisomer Peak 2 558.58 559 (M + H)⁺ 60

Single atropisomer Peak 4 589.00 569 (M + H − H₂O)⁺ 61

Single atropisomer Peak 2 589.00 569 (M + H − H₂O)⁺ 62

Single atropisomer Peak 2 575.63 576 (M + H)⁺ 63

Single atropisomer Peak 3 575.04 575 (M + H)⁺ 64

Single atropisomer Peak 2 575.04 575 (M + H)⁺ 65

Single atropisomer Peak 4 575.04 575 (M + H)⁺ 66

Single atropisomer Peak 1 550.59 533 (M + H − H₂O)⁺ 67

Single atropisomer Peak 1 558.58 559 (M + H)⁺ 68

Single atropisomer Peak 2 558.58 559 (M + H)⁺ 69

Single atropisomer Peak 1 558.58 559 (M + H)⁺ 70

Mixture of four atropisomers 540.52 541 (M + H)⁺ 71

Single atropisomer 567.04 549 (M + H − H₂O)⁺ 72

Single atropisomer Peak 2 578.03 560 (M + H − H₂O)⁺ 73

Single atropisomer Peak 1 572.54 555 (M + H − H₂O)⁺ 74

Single atropisomer Peak 2 568.58 551 (M + H − H₂O)⁺

Comparative Example 757-(2-Hydroxypropan-2-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-carbazole-1-carboxamide

Comparative Example 75 was disclosed in U.S. Pat. No. 8,084,620 asExample 76-15 and was prepared according to the procedure describedtherein.

Comparative Example 767-(2-Hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

Comparative Example 76 was disclosed in WO 2011/159857 as Example 38 andwas prepared according to the procedure described therein.

Biological Assays

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

Human Recombinant Btk Enzyme Assay

To V-bottom 384-well plates were added test compounds, human recombinantBtk (1 nM, Invitrogen Corporation), fluoresceinated peptide (1.5 μM),ATP (20 μM), and assay buffer (20 mM HEPES pH 7.4, 10 mM MgCl₂, 0.015%Brij 35 surfactant and 4 mM DTT in 1.6% DMSO), with a final volume of 30μL. After incubating at room temperature for 60 min, the reaction wasterminated by adding 45 μL of 35 mM EDTA to each sample. The reactionmixture was analyzed on the Caliper LABCHIP® 3000 (Caliper, Hopkinton,Mass.) by electrophoretic separation of the fluorescent substrate andphosphorylated product. Inhibition data were calculated by comparison tono enzyme control reactions for 100% inhibition and no inhibitorcontrols for 0% inhibition. Dose response curves were generated todetermine the concentration required for inhibiting 50% of kinaseactivity (IC₅₀). Compounds were dissolved at 10 mM in DMSO and evaluatedat eleven concentrations.

Ramos FLIPR Assay

Ramos RA1 B cells (ATCC CRL-1596) at a density of 2×10⁶ cells/mL in RPMIminus phenol red (Invitrogen 11835-030) and 50 mM HEPES (Invitrogen15630-130) containing 0.1% BSA (Sigma A8577) were added to one halfvolume of calcium loading buffer (BD bulk kit for probenecid sensitiveassays, #640177) and incubated at room temperature in the dark for 1hour. Dye-loaded cells were pelleted (Beckmann GS-CKR, 1200 rpm, roomtemperature, 5 min) and resuspended at room temperature in RPMI minusphenol red with 50 mM HEPES and 10% FBS to a density of 1×10⁶ cells/mL.150 μL aliquots (150,000 cells/well) were plated into 96 wellpoly-D-lysine coated assay plates (BD 35 4640) and briefly centrifuged(Beckmann GS-CKR 800 rpm, 5 min, without brake). Next, 50 μL compounddilutions in 0.4% DMSO/RPMI minus phenol red+50 mM HEPES+10% FBS wereadded to the wells and the plate was incubated at room temperature inthe dark for 1 hour. The assay plate was briefly centrifuged as aboveprior to measuring calcium levels.

Using the FLIPR1 (Molecular Devices), cells were stimulated by addinggoat anti-human IgM (Invitrogen AHI0601) to 2.5 μg/mL. Changes inintracellular calcium concentrations were measured for 180 seconds andpercent inhibition was determined relative to peak calcium levels seenin the presence of stimulation only.

Jak2 Tyrosine Kinase Assay

Compounds with activity against Jak2 tyrosine kinase have been observedto cause thrombocytopenia, anemia and neutropenia in human patients inclinical trials (see, for example, Pardanani, A., Leukemia, 26:1449-1451(2012)). Jak2 signaling occurs thru EPO and TPO, which controlerythrocyte and platelet proliferation, respectively. Thus, inhibitionof Jak2 tyrosine kinase can potentially lead to side-effects in theclinic. Btk inhibitors with improved selectivity over Jak2 tyrosinekinase are desired in order to minimize off target side-effects relatedto the inhibition of Jak2 tyrosine kinase.

The assays were performed in V-bottom 384-well plates. The final assayvolume was 30 μl prepared from 15 μl additions of enzyme and substrates(fluoresceinated peptide and ATP) and test compounds in assay buffer(100 mM HEPES pH 7.4, 10 mM MgCl₂, 25 mM beta-glycerolphosphate, 0.015%Brij 35 surfactant and 4 mM DTT). The reaction was initiated by thecombination of Jak2 tyrosine kinase with substrates and test compounds.The reaction mixture was incubated at room temperature for 60 minutesand terminated by adding 45 μL of 35 mM EDTA to each sample. Thereaction mixture was analyzed on the Caliper LABCHIP® 3000 byelectrophoretic separation of the fluorescent substrate andphosphorylated product. Inhibition data were calculated by comparison tono enzyme control reactions for 100% inhibition and vehicle-onlyreactions for 0% inhibition. The final concentration of reagents in theassays is ATP, 30 μM; Jak2 fluorescent peptide, 1.5 μM; Jak2, 1 nM; andDMSO, 1.6%. Dose response curves were generated to determine theconcentration required inhibiting 50% of kinase activity (IC₅₀).Compounds were dissolved at 10 mM in DMSO and evaluated at elevenconcentrations, each in duplicate. IC₅₀ values were derived bynon-linear regression analysis.

Whole Blood Assay of BCR-Stimulated CD₆₉ Expression on B Cells

The efficacy of Btk inhibitor compounds in suppressing CD₆₉ expressionon B cells human in whole blood assays is useful for predictingefficacious doses in the clinic and minimizing potential side-effects.Btk inhibitor compounds having higher activity in the whole blood CD₆₉expression assay are expected to require lower doses than compoundshaving lower activity, and are expected to cause fewer unwantedside-effects. (Uetrecht, Chem. Res. Toxicol., 12:387-395 (1999);Nakayama, Drug Metabolism and Disposition, 37(9):1970-1977 (2009);Sakatis, Chem. Res. Toxicol. (2012)).

To measure BCR-stimulated B cells, ACD-A human whole blood was treatedwith various concentrations of test compound and stimulated with 30μg/mL AffiniPure F(ab′)2 fragment goat anti human IgM (Jackson109-006-1299—endotoxin cleared) and 10 ng/mL human IL-4 (PeproTech200-04) for 18 h at 37° C. with agitation. The cells were blocked withhuman gamma globulin (Jackson 009-000-002) and stained withFITC-conjugated mouse anti-human CD₂₀ (BD Pharmingen 555622) andPE-conjugated mouse anti-human CD₆₉ monoclonal antibody (BD Pharmingen555531), lysed and fixed, then washed. The amount of CD₆₉ expression wasquantitated by the median fluorescence intensity (MFI) after gating onthe CD₂₀-positive B cell population as measured by FACS analysis.

In the whole blood assay of BCR-Stimulated CD₆₉ expression on B cells,increased efficacy of a Btk inhibitor compound is indicated by a lowerCD₆₉ IC₅₀ value.

TABLE 11 Jak2 Ratio of IC₅₀ Btk IC₅₀ value IC₅₀ value Jak2/Btk CD69values Example (nM) (nM) IC₅₀ values (nM) 1 2.1 >2000 >950 190 2 1.12000 1800 90 3 1.0 2000 2000 130 4 1.3 350 270 180 5 2.1 >2000 >950 1706 1.1 1500 1400 100 7 0.81 1600 2000 130 8 0.65 >2000 >3100 75 90.62 >2000 >3200 76 10 0.83 >2000 >2400 110 11 0.40 910 2300 65 12 1.81900 1100 190 13 2.9 570 200 140 14 1.2 300 250 20 15 1.0 2400 2400 17016 0.27 1900 7000 120 17 0.59 170 290 120 18 0.65 2200 3400 56 19 0.452000 4400 91 20 0.46 1200 2600 16 21 0.48 760 1600 17 22 0.33 1700 5200120 23 0.44 440 1000 98 24 0.33 1800 5500 21 25 0.90 >2000 >2200 200 261.2 7500 6300 160 27 2.2 >2000 >910 150 28 0.54 32000 59000 90 29 0.66790 1200 240 30 0.22 1300 5900 64 31 0.19 1300 6800 37 32 0.55 1400 2500160 33 0.26 970 3700 24 34 0.85 370 440 98 35 0.25 800 3200 31 36 0.28450 1600 28 37 0.91 630 690 200 38 0.34 300 880 53 39 0.31 370 1200 13040 0.46 830 1800 19 41 0.20 800 4000 22 42 2.0 1200 600 210 43 0.47 20004300 71 44 4.7 710 150 160 45 0.45 3700 8200 68 46 1.5 2000 1300 88 470.35 1800 5100 27 48 0.33 1100 3300 25 49 0.77 >2000 >2600 17 50 0.321200 3800 120 51 0.30 >2000 >6700 190 52 0.48 1100 2300 25 53 1.1 22002000 110 54 0.35 1200 3400 10 55 0.26 9000 35000 44 56 0.62 >2000 >3200140 57 0.25 270 1100 54 58 0.84 13000 15000 240 59 0.90 >2000 >2200 26060 0.18 270 1500 57 61 1.4 1900 1400 93 62 0.41 >2000 >4900 74 63 0.4511000 24000 190 64 0.34 >2000 >5900 88 65 0.46 >2000 >4300 110 66 0.34290 850 89 67 0.49 16000 33000 160 68 0.56 350 630 75 69 0.84 9500 11000150 70 0.59 550 930 66 71 0.41 800 2000 240 72 0.49 770 1600 200 73 0.26580 2200 21 74 0.79 4300 5400 180 Comparative 2.6 240 92 650 Example 75Comparative 6.9 200 29 — Example 76

The compounds of the present invention, as exemplified by Examples 1 to74, have been compared to Comparative Examples 75 and 76, disclosed inU.S. Pat. No. 8,084,620 and WO 2011/159857, respectively, and have beenfound to be advantageous. The compounds of the present invention havethe surprising advantage of the combination of Btk inhibition activityand improved kinase selectivity of Btk inhibition activity over Jak2inhibition activity. As shown in Table 11, in the reported tests,Examples 1 to 74 show the surprising advantage of the combination ofefficacy of Btk inhibition activity and improved kinase selectivity ofBtk inhibition activity over Jak2 inhibition activity, as characterizedby the ratio of Jak2/Btk IC₅₀ values. Increased selectivity for Btkkinase over Jak2 kinase is indicated by a larger value for the ratio ofthe Jak2/Btk IC₅₀ values. Examples 1 to 74 had Btk IC₅₀ values of lessthan 5 nM and ratios of Jak2/Btk IC₅₀ values of 150 and greater. Incontrast, Comparative Examples 75 and 76 had Btk IC₅₀ values of 2.6 and6.9 nM and ratios of Jak2/Btk IC₅₀ values of 92 and 29, respectively.

Additionally, the compounds of the present invention, as exemplified byExamples 1 to 74, also have improved potency in the whole bloodBCR-stimulated CD₆₉ expression assay, compared to Comparative Example75. As shown in Table 11, in the reported tests, Examples 1 to 74 showthe surprising advantage of the combination of efficacy of Btkinhibition activity, improved kinase selectivity of Btk inhibitionactivity over Jak2 inhibition activity, and improved potency in thewhole blood BCR-stimulated CD₆₉ expression assay. Examples 1 to 74 hadBtk IC₅₀ values of less than 5 nM, ratios of Jak2/Btk IC₅₀ values of 150and greater, and CD₆₉ IC₅₀ values of 260 nM and less. In contrast,Comparative Example 75 had a Btk IC₅₀ value of 2.6 nM, a ratio ofJak2/Btk IC₅₀ value of 92, and a CD₆₉ IC₅₀ values of 650 nM.

1. A compound of Formula (I):

wherein: the two dotted lines represent either two single or two doublebonds;

Q is: R₁ is F, Cl, —CN, or —CH₃; R₂ is Cl or —CH₃; R₃ is —C(CH₃)₂OH or—CH₂CH₂OH; R_(a) is H or —CH₃; each R_(b) is independently F, Cl, —CH₃,and/or —OCH₃; and n is zero, 1, or
 2. 2. The compound according to claim1 having the structure of Formula (IA):


3. The compound according to claim 2 wherein: R₁ is F or Cl.
 4. Thecompound according to claim 3 wherein R₃ is —C(CH₃)₂OH.
 5. The compoundaccording to claim 1 having the structure of Formula (IB):


6. The compound according to claim 5 wherein: R₁ is F or Cl.
 7. Thecompound according to claim 6 wherein R₃ is —C(CH₃)₂OH.
 8. (canceled) 9.(canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 14. The compound according toclaim 1 having the structure:


15. The compound according to claim 1 having the structure:


16. The compound according to claim 1 having the structure: